The continued emergence of multi-drug-resistant bacteria is a major public health concern. The identification and development of new antibiotics, especially those with new modes of action, is imperative to help treat these infections. This review lists the 22 new antibiotics launched since 2000 and details the two first-in-class antibiotics, fidaxomicin (1) and bedaquiline (2), launched in 2011 and 2012, respectively. The development status, mode of action, spectra of activity, historical discovery and origin of the drug pharmacophore (natural product, natural product derived, synthetic or protein/mammalian peptide) of the 49 compounds and 6 β-lactamase/β-lactam combinations in active clinical development are discussed, as well as compounds that have been discontinued from clinical development since 2011. New antibacterial pharmacophore templates are also reviewed and analyzed.
Antibiotics have saved countless lives since the discovery of the sulfonamides and β-lactams in the 1930s. These breakthrough discoveries initiated a “golden era” of antibiotic research that lasted 40 years, during which time most current classes of antibiotics were discovered. However, from the early 1970s to 1999 the innovative antibiotic pipeline dried up. All newly launched antibiotics were analogues of existing drugs except for mupirocin, a Gram-positive only topical antibiotic launched in 1985. Since 2000, the situation has improved, with five more new classes of antibiotics launched (Table 1): linezolid (systemic, approved 2000), daptomycin (systemic, approved 2003), retapamulin (topical, approved 2007), fidaxomicin (1; Clostridium difficile infections, approved 2010) and bedaquiline (2; systemic, approved 2012). Bedaquiline is noteworthy as it was fast-tracked through clinical trials for use in combination with other drugs to treat tuberculosis (TB). Although the launch of these novel antibiotics is a step forward, it must be noted that all of these new antibiotic classes are limited to the treatment of Gram-positive infections with new therapies capable of treating Gram-negative infections desperately needed.
Recent years have seen increasing attention drawn to the convergence of events that may portend a return to the pre-antibiotic era: the increasing threat of drug-resistant ‘superbugs’, the dearth of new classes of antibiotics and the disengagement of most pharmaceutical companies from antibiotic research because of economic and regulatory challenges. Attempts to highlight the potentially disastrous outcomes are ongoing, including the well-publicized annual report of the Chief Medical Officer of the United Kingdom in March 2013, which addressed the “very real threat” of antimicrobial resistance.1 Similar discussions in scientific journals since our last review in 20112 include both general overviews of the issues,3, 4 as well as articles that address more specific areas of concern, including mechanisms of antibiotic resistance,5 antibiotic resistance evolution due to sublethal drug concentrations,6 environmental7 or antibiotic8 contributions to resistance development, the overuse of antibiotics in agriculture,9 surveillance programs monitoring worldwide increases in resistance,10 and regulatory hurdles for antibiotic drugs.11 These issues have also been captured in articles in the popular press, such as a 2012 article in The Atlantic on: “The Rise of Antibiotic Resistance: Consequences of FDA’s Inaction”12 and articles in The New York Times such as “Deadly Bacteria That Resist Strongest Drugs Are Spreading”13 and “Let’s Gang Up on Killer Bugs”.14
There have been a number of significant developments in improving the atmosphere for antibiotic research, including the US Generating Antibiotic Incentives act (automatic priority review and an additional 5–7 years of market exclusivity for qualified infectious disease products), and the Innovative Medicines Initiative New Drugs for Bad Bugs (IMI ND4BB), a $280 million fund to support the clinical development of new antibiotics and conduct basic research into how antibiotics penetrate Gram-negative bacteria.15 Other incentives have also been proposed.16, 17, 18, 19 In 2010, the Infectious Diseases Society of America launched the 10 × ’20 Initiative to develop 10 new safe and efficacious systemically administered antibiotics by 2020.20, 21, 22 This initiative is focused on developing novel antibiotics to treat Gram-negative bacteria, which are more challenging targets than Gram-positive bacteria because of the presence of an outer membrane permeability barrier, multiple efflux pumps, and antibiotic- and target-modifying enzymes.23, 24, 25 Although a 2013 update on the progress of the 10 × ’20 Initiative found that there have been advances in some areas, it was reiterated that many of the original obstacles remained.26
The commercial landscape for antibiotic development in the last few years has not been encouraging. In 1990, there were 18 large pharmaceutical companies actively engaged in antibiotic research and development, whereas today there are just four: AstraZeneca (London, UK), Novartis (Basel, Switzerland), GSK (London, UK) and Sanofi-Aventis (Paris, France).16 Depressingly, AstraZeneca CEO Pascal Soriot laid out plans on 21 March 2013 to reduce its future investments in antibiotics,27 whereas a former major antibiotics player, Pfizer (Groton, CT, USA), closed its antibiotic R&D center in Connecticut in 2011.28 These decisions highlight the reluctance of drug firms to invest in an area with comparably poor returns and costly phase-III trials that have onerous recruitment requirements needed to fulfill the non-inferiority conditions currently mandated by the Food and Drug Administration (FDA). This is despite an historically high approval rate of antibiotics following the successful completion of phase-I studies.29
The net present value for an antibiotic to treat acute infections does not compare to the values ascribed to most other therapeutic areas. Antibiotics are only administered for a few weeks and are priced in the range of hundreds of dollars per day (for example, linezolid 600 mg tablet for $134, daptomycin 500 mg for $362 and Synercid 150–350 mg for $247)30, 31, 32 with some widely used older antibiotics available at much lower prices (for example, vancomycin 1000 mg for $5).33, 34 In contrast, long-term therapies such as cholesterol-lowering drugs and anti-hypertensive agents are taken daily for many years or decades, whereas biological anti-cancer agents and orphan disease treatments are often priced at >$10 000 per treatment. Put simply, we ascribe almost no monetary value to antibiotics in society today and we need a new financial way forward to incentivize the discovery, development and registration of new antibiotics. One solution is government intervention, as suggested in a report from the London School of Economics that proposed a push-pull mechanism to provide a global incentive for more investment in antibiotic R&D.35 This incentive would be limited to potential drugs that meet stringent criteria for medical need and probability of successful registration. This would lead to a positive net present value for a new antibiotic. The additional risk of slow uptake (often the case for new antibiotics on the market) is ameliorated, as is the development risk at phase-III as the costs are borne by the government. When full economic costing is considered for the estimated two million patients in the Europe (EU) every year that catch hospital-acquired infections (of which 175 000 die), the government receives a significant economic return on investment, in addition to the social and health benefits to society. We also need to think long and hard about antibiotic drug pricing and whether it is ethically acceptable to pay so much for life-extending and lifestyle-associated drugs, but still expect to pay peanuts for life-saving antibiotics. The potential for government contributions to have a key role in the future is illustrated by the May 2013 announcement of a $200 million public–private partnership between the US government Biomedical Advanced Research and Development Authority (BARDA) and GSK to study potential new drugs to treat both conventional pathogens and those that could be developed into weapons.36 This is on top of a number of recent BARDA awards to smaller companies to develop antibiotics.37, 38, 39
One facet of antimicrobial therapy that is often overlooked in discussions on antimicrobial resistance to antibiotics is that there are emerging alternative approaches toward treating bacterial infections. Although not discussed in this article, non-antibiotic-based therapies, such as vaccines, neutralizing antibodies, probiotic therapy, phage therapy, immune stimulation and virulence factor neutralization, also show promise for preventing or treating drug-resistant microbial infections.
This review is an update of our 2011 review2 and details recently launched antibiotics (Table 1, Figures 1 and 2) and compounds and β-lactam/β-lactamase inhibitor combinations undergoing clinical development in phase-I, -II or -III trials or under regulatory evaluation as of May 2013 (Tables 2, 3, 4, Figures 3, 4, 5, 6, 7, 8, 9, 10). These descriptions include their development status, mode of action, spectra of activity, historical discovery and origin of the drug pharmacophore: natural product (NP), NP-derived, synthetic (S) or protein/mammalian peptide (P). New clinical trials of approved drugs including new formulations are not discussed in this review. The ClinicalTrials.gov NCT codes are listed in parentheses for each trial and trials not in this database are referenced. These data were obtained by analyzing the journal literature and internet resources such as company web pages, clinical trial registers and biotechnology-related newsletters. Compounds have been excluded from this review if there has been no development activity reported since the beginning of 2010 (Table 5). Every endeavor has been undertaken to ensure that these data are accurate, but it is possible compounds undergoing early clinical development with limited information in the public domain have been overlooked.
The drug development and approval process as well as commonly used abbreviations associated with antibiotic development are as follows:
Before clinical trials can start, an Investigational New Drug Application must be approved by the US FDA, European Medicines Agency (EMA), Japanese Pharmaceuticals and Medical Devices Agency or equivalent national agency. Upon successful completion of phase-III clinical trials, a New Drug Application (NDA: FDA and Pharmaceuticals and Medical Devices Agency) or a Marketing Authorization Application (MAA: EMA) must be approved to be able to market the drug. It is also possible to obtain approval for desperately required drugs under the FDA’s accelerated approval program after successful completion of phase-II trials. Some infectious disease antibiotic development programs are assisted by the BARDA, a US government agency mandated to provide an integrated, systematic approach to the development and purchase of the necessary vaccines, drugs, therapies and diagnostic tools for public health medical emergencies. Others are assisted by the Division of Microbiology and Infectious Diseases within the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, and by Europe’s Innovative Medicines Initiative.
Antibacterial clinical trial indications generally fall within one of the following infection categories: C. difficile infections (CDIs), C. difficile-associated diarrhea (CDAD), skin and skin structure infections (SSSi), which are further divided into complicated (cSSSi), uncomplicated (uSSSi) and acute bacterial (ABSSSi), community (CAP)-/hospital-acquired pneumonia, community-acquired bacterial pneumonia (CABP), urogenital gonorrhea, irritable bowel syndrome, ophthalmic indications, such as acute otitis media, urinary tract infections (UTIs) and complicated UTIs (cUTIs), complicated intra-abdominal infections (cIAIs), skin infections, such as acne, rosacea and impetigo, and TB.
Other abbreviations: diazabicyclooctane (DBO), early bactericidal activity (EBA), EU, Gram-positive (G+ve), Gram-negative (G−ve), intravenous (IV), Initial Public Offering, NP, minimum inhibitory concentration, multi-drug resistant (MDR), lipopolysaccharide (LPS), penicillin-binding protein, protein/mammalian peptide (P), Securities and Exchange Commission, structure–activity relationships, synthetic (S) and United States of America (USA).
Antibacterial Drugs Launched since 2000
Since 2000, 22 new antibiotics (2 NP, 10 NP derived and 10 synthetic) have been launched worldwide (Table 1). Two new antibiotics, fidaxomicin (1) and bedaquiline (2; Figure 2), have been approved since the last review in this series2 and are discussed in detail. There has been a steady launch of antibiotics since 2000, averaging one to two launches per year (Figure 1). Five first-in-class antibiotics have been introduced in this period: linezolid (oxazolidinone, S, 2000), daptomycin (lipopeptide, NP, 2003), retapamulin (pleuromutilin, NP-derived, 2007), fidaxomicin (1; tiacumicin, NP, 2011) and bedaquiline (2; diarylquinoline, S, 2012). The 10 synthetically derived antibiotics are dominated by eight quinolones and this trend is set to continue with six quinolones being evaluated in phase-III (Table 2) and two in phase-II trials (Table 3). Six of the twelve NP and NP-derived antibiotics belong to the β-lactam class with the other six belonging to separate classes. The continued potential of bacteria as a source for antibiotic-lead discovery40 is reinforced by the list of launched antibiotics, with 9 of the 12 NP-derived antibiotic-lead compounds being derived from actinomycetes and 3 from fungi.
Fidaxomicin (1) was developed by Optimer Pharmaceuticals (San Diego, CA, USA) and approved by the US FDA in May 2011 (trade name: Dificid) and by the EMA in December 2011 (trade name: Dificlir) for the treatment of intestinal infections and diarrhea caused by C. difficile.41 C. difficile is a spore-forming Gram-positive anaerobe that can overgrow beneficial and commensal gastrointestinal bacteria, secreting toxins that lead to severe diarrhea, inflammation of the colon, fever, intestinal paralysis and sepsis, which can be lethal.42 C. difficile-associated diarrhea has become the leading cause of hospital-acquired infections, a situation aggravated by increasing outbreaks of hypervirulent strains that overproduce the toxins.43, 44 Fidaxomicin (1) is an actinomycete-derived macrolactone45 that was named tiacumicin B when isolated at Abbott Laboratories, with a patent filed in 198646 and publication in 1987.47, 48 The tiacumicins have identical structures to the lipiarmycins (isolation reported in 197549, 50, 51, 52 and structure in 198753, 54) and the clostomicins (reported in 198655). Fidaxomicin (1) inhibits bacterial RNA polymerase transcription by blocking the initiation of RNA synthesis.56, 57
In late December 2012, the US FDA approved bedaquiline (2; trade name: Sirturo) as part of combination therapy to treat adults with MDR pulmonary TB when other alternatives are not available.58 Bedaquiline (2) was approved after the successful completion of two phase-II clinical trials under the FDA’s accelerated approval program59 and was jointly developed by Tibotec (Beerse, Belgium) and the Global Alliance for TB Drug Development (New York, NY, USA).60, 61 Bedaquiline (2), derived from a series of diarylquinolines discovered62 through whole-cell screening against Mycobacterium smegmatis, specifically targets the oligomeric subunit c of mycobacterial ATP synthase.63, 64
Compounds Undergoing Clinical Evaluation
The compounds currently undergoing clinical trials or under regulatory evaluation for the treatment of bacterial infections as of May 2013 are detailed in the following tables and figures: phase-III/NDA in Table 2 with structures in Figures 3, 4, 5, phase-II in Table 3 with structures in Figures 6, 7, 8 and phase-I in Table 4 with structures in Figures 9 and 10.
Phase-III trials and NDA/MAA applications
NP and NP-derived compounds in phase-III trials
Dalbavancin (3) and oritavancin (4) are semi-synthetic lipoglycopeptide analogs of the vancomycin/teicoplanin class of antibiotics that are designed for IV treatment of Gram-positive infections. These “second-generation” glycopeptides possess additional lipophilic substituents that significantly increase their biological half-life (approximately 200 and 400 h, respectively) and provide additional mechanisms of action beyond simple inhibition of peptidoglycan synthesis.65 Both have had a troubled regulatory and commercial pathway, although there now may be a light at the end of the tunnel. Dalbavancin (3; BI-397), a semi-synthetic derivative of the teicoplanin-like glycopeptide A40926 Factor B, was originally developed by Vicuron Pharmaceuticals,66, 67, 68, 69 which was acquired by Pfizer (Groton, CT, USA) in 2005. Three phase-III trials were successfully completed between 2003 and 2005 but the FDA requested additional non-inferiority data in 2007.65 Little progress was made until 2009, when Durata Therapeutics (Chicago, IL, USA) acquired the program and initiated two additional phase-III trials (NCT01339091 and NCT01431339). In December 201270 and February 2013,71 Durata announced that the DISCOVER 1 and 2 (“Dalbavancin for Infections of the Skin COmpared to Vancomycin at an Early Response”) phase-III studies (573 patients at 92 sites and 739 patients at 139 sites) met their primary end point of non-inferiority, comparing two IV doses of dalbavancin (3) given 1 week apart with twice-daily vancomycin doses for 14 days. The company also indicated it intends to submit an NDA with the FDA by mid-2013 and an MAA with the EMA at year-end 2013.71
Oritavancin (4; LY333328) was initially developed by Eli Lilly in the 1990s and is a semi-synthetic derivative of the vancomycin-like glycopeptide chloroeremomycin.69, 72, 73 InterMune, Inc. acquired the rights in 2001, followed by Targanta Therapeutics in 2005. Two phase-III trials were successfully completed, with the results disclosed in 2001 and 2003, but the FDA rejected an NDA in December 2008 because of concerns over safety and effectiveness.65, 73 In January 2009, Targanta was acquired by the Medicines Company (Parsippany, NJ, USA), which initiated two phase-III trials (NCT01252719 and NCT01252732) for Gram-positive ABSSSi (SOLO I, 968 patients at 46 centers globally, successfully completed by October 2012;74 SOLO II, currently recruiting 960 patients at 100 centers globally with enrollment expected by mid-2013), as well as two phase-I safety trials (NCT01784536 and NCT01762839) to assess cardiotoxicity and CYP450 activity (completed by January 2013).
Omadacycline (5; amadacycline, PTK-0796) is a semi-synthetic tetracycline derivative75, 76 developed by Paratek Pharmaceuticals (Boston, MA, USA) with a complex development history. Omadacycline (5) has been licensed to Bayer (Leverkusen, Germany), Merck (Rahway, NJ, USA) and then Novartis (Basel, Switzerland), who started a phase-III trial for the treatment of cSSSi in 2009 but discontinued the studies in 2011 (NCT00865280). Paratek is planning phase-III trials for omadacycline (5) for the treatment of ABSSSi and CABP using both oral and IV formulations,76 as well as planning studies for the treatment of UTIs. It is presumed that Paratek will fund these studies from a planned initial public offering that was registered with the US Securities and Exchange Commission in September 2012.77
Eravacycline (6; TP-434) is a synthetic tetracycline derivative78, 79, 80 developed by Tetraphase Pharmaceutics (Watertown, MA, USA) that recently entered into a phase-III trial for the treatment of cIAI (NCT01844856) after successfully completing a phase-II trial (NCT01265784). Eravacycline (6) is the first member of the new fluorocycline tetracycline subclass with broad-spectrum activity that includes bacteria with tetracycline-specific efflux and ribosomal protection. As with other tetracyclines, eravacycline (6) inhibits bacterial protein synthesis.81
Solithromycin (7; CEM-101) is a semi-synthetic 2-fluoroketolide being developed by Cempra Pharmaceuticals (Chapel Hill, NC, USA) that is currently being evaluated in a phase-III trial for the treatment of CABP (NCT01756339) and a phase-II trial for the treatment of uncomplicated urogenital gonorrhea (NCT01591447). Solithromycin (7), which was discovered by Optimer Pharmaceuticals (San Diego, CA, USA)82 and then licensed to Cempra in 2006, is a protein synthesis inhibitor that has broad-spectrum antibacterial activity including many ketolide/macrolide-resistant strains.83, 84, 85 Solithromycin (7) differs from telithromycin, a ketolide launched in the EU (2001) and USA (2004) that has had some safety issues including visual disturbances and hepatotoxicity. These side effects could be due to inhibition of nicotinic acetylcholine receptors via the pyridine moiety on its side chain.86 Solithromycin (7) does not contain the pyridine moiety and, as a consequence, is not predicted to display these side effects. In May 2013, Cempra was awarded $58 million to develop 7 for pediatric use and for biodefense by BARDA.39
Surotomycin (8; CB-183 315) is a semi-synthetic daptomycin derivative87 that is being evaluated by Cubist Pharmaceuticals (Lexington, MA, USA) in two identical phase-III trials (NCT01597505 and NCT01598311) for the treatment of C. difficile-associated diarrhea. Surotomycin (8) has good bactericidal activity against a panel of C. difficile strains that include the highly virulent NAP1 strain, has negligible systemic absorption and has a minor impact on the levels of key normal bowel bacteria such Bacteroides spp.88, 89, 90
Synthetic compounds in phase-III trials
Tedizolid phosphate (9a)91, 92, 93 (torezolid phosphate, TR-701, DA-7218) is an oxazolidinone being developed by Trius Therapeutics (San Diego, CA, USA) that has completed a phase-III trial for the treatment of Gram-positive ABSSSi (NCT01170221).94 Discovered by Dong-A Pharmaceutical (Seoul, South Korea), it is a pro-drug that is dephosphorylated in vivo to give tedizolid (9b), which is active against various Gram-positive bacteria including linezolid-resistant strains.95 Like linezolid, tedizolid (9b) binds to the 50S ribosome preventing the formation of the 70S initiation complex, which in turn blocks the initiation of protein synthesis.96
Delamanid (10; OPC-67683) is being evaluated by Otsuka Pharmaceutical Co. (Tokyo, Japan) in a phase-III trial for the treatment of MDR TB in combination with other TB drugs over 6 months (NCT01424670). Otsuka has filed an MAA with the EMA in 2011 and a Pharmaceuticals and Medical Devices Agency in March 2013 in Japan on the basis of phase-II data including trial NCT00685360.97 Delamanid (10)98, 99 is derived from the bicyclic nitroimidazole CGI-17341,100, 101 which was a promising TB lead compound dropped from development because of mutagenicity concerns. Delamanid (10) and PA-824 (33, phase-II section, Figure 7) are both non-mutagenic in the Ames mutagenicity assay. Both 10 and 33 are pro-drugs that are reductively activated by a deazaflavin (F420)-dependent nitroreductase.101
Thioureidoiminomethylpyridinium perchlorate (11; Perchlozone) is under development by JSC Pharmasyntez (Moscow, Russia) and has completed a phase-II/III trial for the treatment of patients with TB. The perchlorate salt of thioureidoiminomethylpyridine (11) was synthesized at the Siberian Division of the Russian Academy of Sciences (Novosibirsk, Russia)102, 103 and is the salt form of thioureidoiminomethylpyridine, which was discovered to have anti-TB activity in the early 1950s.104, 105
SQ109 (12) is an ethambutol analog developed by the NIAID and Sequella (Rockville, MD, USA) that has recently completed a phase-II trial for EBA in patients with pulmonary TB (NCT01218217). In December 2012, SQ109 (12) started a phase-II/III trial in collaboration with Infectex (Moscow, Russia) for the treatment MDR-TB.106 SQ109 (12) was chosen as the lead candidate after the synthesis and biological evaluation of 63 000 analogs synthesized using a combinatorial solid-phase approach.107 Although SQ109 (12) was designed as an ethambutol analogue, it was recently shown that these compounds differ in their mode of action with SQ109 (12) inhibiting MmpL3, a transporter of mycobacterial trehalose monomycolate.108 An X-ray structure of SQ109 (12) binding to Staphylococcus aureus dehydrosqualene synthase has also been published.109
There are currently four fluoroquinolones, finafloxacin (13), delafloxacin (14), avarofloxacin (15) and zabofloxacin (16), and two quinolones, nemonoxacin (17) and ozenoxacin (18), being evaluated in phase-III trials. Quinolone antibiotics kill bacteria through a dual mechanism of DNA gyrase (GyrA) and topoisomerase IV (ParC) inhibition, with the GyrA/ParC activity ratios depending on the compound and microorganism target.110
Finafloxacin (13; BAY 35–3377) is being tested in phase-III trials by MerLion Pharmaceuticals (Singapore, Singapore) for the treatment of acute otitis media (inner and outer ear infections).111 Finafloxacin (13) is also being evaluated in a phase-II trial to treat patients with complicated UTI112 and has previous completed phase-II trials for uncomplicated UTI (NCT00722735) and Helicobacter pylori eradication (NCT00723502). The pre-clinical development of finafloxacin (13) was focused on reducing toxicity issues associated with other fluoroquinolones and an excellent safety profile has been observed in the clinical trials to date.113, 114 Finafloxacin (13) was also highly effective in in vivo infection models and this could be due to the improved activity at slightly acidic pH, which is more representative of physiological conditions.115, 116, 117, 118 This is in contrast to marketed quinolones that are less efficacious at acidic pH.119
Delafloxacin (14; RX-3341, WQ-3034, ABT-492) is being evaluated by Rib-X Pharmaceuticals (New Haven, CT, USA) for the treatment of ABSSSi, with patients soon to be enrolled in a phase-III trial (NCT01811732). Similar to finafloxacin (13), delafloxacin (14) displays enhanced activity against Gram-positive bacteria at more acidic pH (pH 5). This has been proposed to be due to the lack of a basic residue in the pendant heterocycle providing an overall weakly anionic character.120
Avarofloxacin (15; JNJ-32729463, JNJ-Q2) is being developed by Furiex Pharmaceuticals, Inc (Morrisville, NC, USA) in phase-III trials for the treatment of irritable bowel syndrome (NCT01553747 and NCT01553591). Avarofloxacin (15) has successfully completed phase-II trials for cSSSi (NCT01130272) and irritable bowel syndrome (NCT01128530), whereas a phase-II trial for CABP was terminated because of slow enrollment (NCT01198626). Avarofloxacin (15) displays equipotent activity against GyrA and ParC, which has been suggested to improve the spectrum of activity and lower the potential for resistance.121 In addition, the presence or absence of the NorA efflux pump did not alter the minimum inhibitory concentrations of avarofloxacin (15), which suggested reduced susceptibility to bacterial efflux.122
Zabofloxacin (16; PB-101, DW-224a) is undergoing phase-III trials conducted by Dong Wha Pharmaceutical (Seoul, South Korea) for the treatment of patients with acute bacterial exacerbation of chronic obstructive pulmonary disease (NCT01658020). Dong Wha had licensed zabofloxacin (16) to IASO Pharma, Inc. (San Diego, CA, USA, formally Pacific Beach Biosciences) but their phase-III trial for CAP was halted in May 2012 due to financial reasons (NCT01081964). Zabofloxacin (16) has broad-spectrum antibacterial activity123, 124 and inhibits both GyrA and ParC.125
Nemonoxacin (17; TG-873870) is being evaluated in a phase-III trial by TaiGen Biotechnology Co., Ltd. (Taipei, Taiwan) for the treatment of patients with CAP (NCT01529476). TaiGen secured the full worldwide rights to nemonoxacin (17) in December 2011, after originally licensing it from Procter & Gamble Pharmaceuticals, which was acquired by Warner Chilcott (Rockaway, NJ, USA) in October 2009. Nemonoxacin (17) is a non-fluorinated quinolone that has broad-spectrum activity against susceptible and resistant Gram-positive and Gram-negative strains.126, 127
Ozenoxacin (18; T-3912) recently completed a phase-III trial by Ferrer Internacional S.A. (Barcelona, Spain) for patients with impetigo (NCT01397461), whereas a phase-III trial for acne by Maruho Co. (Osaka, Japan) is ongoing.128 Ozenoxacin (18) is also a non-fluorinated quinolone with broad-spectrum activity against a variety of susceptible and resistant Gram-positive bacteria.129
β-Lactam/β-lactamase inhibitor combinations in phase-III trials
The β-lactam antibiotics, which include penicillins, cephalosporins and carbapenems, have been one of the most successful antibiotic classes ever discovered. A common resistance mechanism for β-lactams is ring opening by β-lactamase enzymes, inactivating the antibiotics and rendering them unable to inhibit the bacterial penicillin-binding proteins. The co-administration of a β-lactamase inhibitor with a β-lactam considerably prolongs the antibiotic activity. The first β-lactamase inhibitor, clavulanic acid,130, 131, 132 was isolated from Streptomyces clavuligerus and is still used today in combination with amoxicillin, which is most commonly known under GSK’s trade name Augmentin. The new β-lactam/β-lactamase inhibitor combinations have been recently reviewed.133, 134
CXA-201 (ceftolozane (19; CXA-101, FR264205)/tazobactam (20)) is a cephalosporin/β-lactamase inhibitor combination that is being developed by Cubist Pharmaceuticals (Lexington, MA, USA) in phase-III trials for cUTI (NCT01345929) and pyelonephritis (NCT01345955) and in two phase-III trials for cIAI (NCT01445665 and NCT01445678). CXA-201 is administered IV and has activity against Gram-negative bacteria including MDR Pseudomonas aeruginosa. Ceftolozane (19) is a cephalosporin discovered by Astellas (Tokyo, Japan) with broad-spectrum Gram-negative activity,135, 136, 137 whereas tazobactam (20) is a clavulanic acid-type β-lactamase inhibitor first approved in 1992 in combination with piperacillin.138, 139
CAZ104 (ceftazidime (21)/avibactam (22; NXL104, AVE1330A)) is a cephalosporin/β-lactamase inhibitor combination140 that is being assessed by AstraZeneca (London, UK) in three phase-III trials for the treatment of cUTI (NCT01644643, NCT01599806 and NCT01595438). Ceftazidime (21) is a third-generation cephalosporin first launched in 1983 with activity against Gram-negative bacteria including the Enterobacteriaceae and P. aeruginosa.141 Avibactam (22) is a non-β-lactam β-lactamase inhibitor of the DBO class, which displays activity against class A and C serine β-lactamases.142, 143, 144 Avibactam (22) was discovered by Hoechst Marion Roussel, which eventually formed part of Sanofi-Aventis (Paris, France). Sanofi-Aventis spun out anti-infective discovery into Novexel in 2004, which was acquired by AstraZeneca (London, UK) in 2010. Avibactam (22) is also being evaluated in phase-II and phase-I trials in combination with ceftaroline (23; Figure 8) and aztreonam (24; Figure 10), respectively.
NP and NP-derived compounds in phase-II trials
LFF-571 (25) is a semi-synthetic derivative of the thiopeptide GE2270-A being developed by Novartis (Basel, Switzerland) and is currently undergoing phase-II testing for the treatment of moderate CDIs (NCT01232595). LFF-571 (25) has broad-spectrum activity against Gram-positive bacteria including anaerobic and aerobic intestinal bacteria145 and was well tolerated in a phase-I trial.146 GE2270-A is an actinomycetes-derived antibiotic first described by the Lepetit Research Institute (formally Gerenzano, Italy) in 1991 that inhibited protein synthesis via bacterial elongation factor Tu (EF-Tu). Scientists at Novartis recognized the potential of GE2270-A, leading to the synthesis of the dicarboxy derivative LFF-571 (25), which was considerably more soluble than GE2270-A.147 LFF-571 (25) also inhibits bacterial EF-Tu.148
Auriclosene (26; NVC-422, N,N-dichloro-2,2-dimethyltaurine) is an N-dichlorotaurine analog being evaluated in phase-II trials by NovaBay Pharmaceuticals, Inc. (Emeryville, CA, USA) to prevent urinary catheter blockage and encrustation (NCT01243125), as an ophthalmic solution for the treatment of adenoviral conjunctivitis (NCT01532336) and for the treatment of impetigo in partnership with Galderma SA (Lausanne, Switzerland).149 Auriclosene (26) has also completed a phase-II trial for the treatment of bacteriuria in catheterized patients (NCT00781339). Auriclosene (26) was designed to be a more stable derivative of the naturally occurring oxidant N-dichlorotaurine;150, 151, 152 the N-chloramine antibiotic class has been recently reviewed.153
Sarecycline (27; P005672, PTK-AR01), a semi-synthetic tetracycline derivative154, 155 discovered by Paratek Pharmaceuticals (Boston, MA, USA) and licensed156 to Warner Chilcott (Rockaway, NJ, USA) in July 2007, recently completed a phase-II trial for the treatment of facial acne vulgaris (NCT01628549).
BC-3781 (28), a semi-synthetic pleuromutilin157, 158 derivative discovered by Nabriva Therapeutics AG (Vienna, Austria), is being developed in collaboration with Forest Laboratories (New York, NY, USA). It completed a phase-II trial for ABSSSi in 2012 (NCT01119105).159 BC-3781 (28) is a protein synthesis inhibitor and displays antibacterial activity against skin and respiratory pathogens such as S. aureus, Enterococcus faecium, Streptococcus pneumoniae, Haemophilus influenzae, C. difficile, Moraxella catarrhalis, Legionella pneumophila and Mycoplasma pneumoniae.158, 160, 161
Plazomicin (29; ACHN-490) is a semi-synthetic derivative162 of the aminoglycoside sisomicin163, 164 developed by Achaogen, Inc. (South San Francisco, CA, USA) that has completed phase-II trials for the treatment of UTI and pyelonephritis (NCT01096849). Plazomicin (29) displays excellent activity against methicillin-resistant S. aureus (MRSA)165 and the MDR Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae and Enterobacter spp.166 Plazomicin (29) displayed similar activity against P. aeruginosa as amikacin, another semi-synthetic aminoglycoside, but lower than average activity against Acinetobacter baumannii compared with other aminoglycosides.167 The biological activity and spectrum of activity of plazomicin (29) has been recently reviewed.168
GSK1322322 (30), under development by GlaxoSmithKline (GSK; London, UK), has completed a phase-II trial for ABSSSi (NCT01209078) with two further phase-I trials enrolling volunteers (NCT01803399 and NCT01818011). GSK1322322 (30) displays promising activity against the Gram-positive pathogens such as S. aureus, S. pneumoniae, Streptococcus pyogenes, as well as against the Gram-negatives H. influenzae and M. catarrhalis.169 It targets bacterial peptide deformylase, a metallo-hydrolase enzyme that catalyzes the removal of formyl groups from N-terminal methionines following translation.170 Two previous peptide deformylase inhibitors, BB83698 and LBM-415, reached phase-I but their development was discontinued.171, 172, 173, 174 These compounds were based on the NP lead, actinonin,175, 176 which was identified by virtual searching for NPs that possessed a hydroxamate metal-chelating group and methionine-like structures as potential peptide deformylase inhibitors.177
Protein/mammalian peptide-derived compounds in phase-II trials
Brilacidin (31; PMX-30063), a membrane targeting arylamide oligomer that was being developed by Polymedix Inc. (Radnor, PA, USA), recently completed a phase-IIa trial for the treatment of ABSSSi (NCT01211470). However, the future development of brilacidin (31) is in doubt as Polymedix filed for bankruptcy on 1 April 2013 and there have been reports of possible toxicity concerns.178 Brilacidin (31) is a member of the family of arylamide foldamers that was designed to mimic cationic antimicrobial peptides and had shown bactericidal activity against both Gram-positive and Gram-negative bacteria.179, 180, 181
LTX-109 (32; Lytixar) is another cationic peptide mimic58 that is being developed by Lytix Biopharma AS (Oslo, Norway) in a phase-II trial for the treatment of impetigo (NCT01803035). LTX-109 (32) has completed a phase-II trial for the treatment of uSSSi (NCT01223222) and a phase-I/II trial for nasal decolonization of S. aureus including MRSA (NCT01158235). LTX-109 (32) is metabolically stable and has rapid bactericidal in vitro activity against both Gram-positive and Gram-negative drug-resistant strains.182 An in-depth study of 32 against a large panel of S. aureus strains, including MRSA, vancomycin-intermediate S. aureus and vancomycin-resistant S. aureus, was reported in 2012.183
DPK-060 (CD-1) is an antimicrobial peptide being developed by Pergamum AB (Solna, Sweden) that has completed phase-II trials for the treatment of external otitis (NCT01447017) and atopic dermatitis (NCT01522391). The structure of DPK-060 has not been published but is likely to be a derivative of the antibacterial domain of kininogen.184, 185, 186
LL-37 (33), the C-terminal peptide of the human antimicrobial cathelicidin peptide hCAP-18, is being developed in a phase-I/II trial for the wound healing in chronic leg ulcers by Pergamum AB (Solna, Sweden).187 Although cathelicidins have been identified in a variety of species, hCAP-18 is the only human cathelicidin and consists of a 30-amino-acid signal peptide domain, a 103-amino-acid cathelicidin domain and a 37-amino-acid C-terminal peptide designated as LL-37.188, 189 LL-37 (33) has broad-spectrum antibacterial activity190 and kills bacteria through membrane disruption.191 Interestingly, LL-37 (33) displayed equipotent activity with its enantiomer D-LL-37, which suggested a nonspecific mode of action, whereas a structure activity relationship study showed that antibacterial activity can be retained down to 19 residues.192
IMX-942 is a five-amino-acid synthetic cationic peptide loosely based on indolicidin, which is derived from bovine neutrophils,193 and the synthetic peptide innate defense regulator-1.194, 195 Inimex Pharmaceuticals, Inc. (Coquitlam, BC, Canada)196 is evaluating IMX-942 in a phase-II clinical trial in combination with a standard antibiotic therapy with severe ABSSSi to investigate whether this combination can shorten clearance time of the bacterial infection in these patients.197 Although the structure and mode of action of IMX-942 has not been published, the anti-inflammatory mode of action of innate defense regulator-1 is via sequestosome-1/p62.195
Synthetic compounds in phase-II trials
PA-824 (34) is a nitroimidazole derivative being tested by the Global Alliance for TB Drug Development (New York, NY, USA) in phase-II trials in combination with other TB drugs (NCT01691534 and NCT01498419). PA-824 (34) was originally synthesized by PathoGenesis Corporation (acquired by Chiron in 2002, who in turn were acquired by Novartis (Basel, Switzerland) in 2006) as an analog of the TB-lead CGI-17341, which was found to be too toxic for further development.198 The mode of action of PA-824 (34) is complex but under anaerobic conditions 34 is reductively activated by a deazaflavin-dependent nitroreductase and then acts as a nitric oxide donor in a similar manner to delamanid (10, phase-III section, Figure 4).199, 200
There are currently three oxazolidinones45, 93, 201 that have been studied in phase-II trials: radezolid (35), sutezolid (36) and posizolid (37). Radezolid (35; RX-1741)202, 203, 204, 205 has completed phase-II studies for the treatment of both cSSSi (NCT00646958) and CAP (NCT00640926) and is similar in structure to tedizolid phosphate (9a), which has completed phase-III studies. Radezolid (35) has activity against Gram-positive bacteria including those with resistance to linezolid, as well activity against some Gram-negatives such as H. influenzae and M. catarrhalis,206 and was rationally designed from the overlap of sparsomycin- and linezolid-binding sites on the 50S ribosomal subunit.202, 203, 207
Sutezolid (36; PNU-100480, PF-02341272) is being developed by Pfizer (Groton, CT, USA) and recently completed a phase-IIa trial looking for EBA in naive patients with drug-sensitive pulmonary TB (NCT01225640). Sutezolid (36) was discovered at Upjohn (now part of Pfizer) and its structure optimized for activity against TB.208 Sutezolid (36) displays promising in vitro and in vivo activity against TB,209, 210 and was well tolerated in phase-I trials.211, 212
Posizolid (37; AZD5847, AZD2563) is an oxazolidinone developed by AstraZeneca (London, UK) that the NIAID is sponsoring in a phase-IIa trial for EBA with newly diagnosed pulmonary TB patients (NCT01516203). Posizolid (37) was originally developed as a broad-spectrum Gram-positive antibiotic213, 214 and was later found to have activity against TB.215
Cadazolid (38; ACT-179811) is a quinolonyl-oxazolidinone chimeric antibiotic being developed by Actelion Pharmaceuticals (Basel, Switzerland) that successfully completed a phase-II trial for the treatment of patients with CDI (NCT01222702) in 2013. Actelion recently announced plans to commence phase-III trials.216 Cadazolid (38) is a potent inhibitor of C. difficile protein synthesis, leading to strong suppression of toxin and spore formation.217, 218
AFN-1252 (39) is being developed by Affinium Pharmaceuticals (Austin, TX, USA) and successfully completed a phase-IIa trial (NCT01519492) as an oral formulation for the treatment of staphylococcal infections in 2012. AFN-1252 (39) disrupts fatty acid biosynthesis by inhibiting staphylococcal FabI,219, 220 an essential enzyme that catalyzes the reduction of trans-2-enoyl-ACP to acyl-ACP in the final step of the fatty acid elongation cycle.221, 222 AFN-1252 (39) is a synthetically derived antibiotic elaborated from a benzodiazepine hit initially identified at GSK (London, UK) using a high-throughput screen looking for inhibitors of S. aureus FabI.29, 223 Structure optimization using X-ray crystal structure-based design led to the identification of a 3,4-dihydro-1,8-naphthyridin-2(1H)-one core, which had selective, potent activity against FabI, and good in vitro and in vivo antibacterial activity with no significant cytotoxicity.223 In 2002, GSK licensed this discovery to Affinium who undertook further structure optimization that culminated in the discovery of AFN-1252 (39).224, 225
CG400549 (40) is being developed by CrystalGenomics, Inc. (Seoul, South Korea) and recently successfully completed a phase-IIa trial for the treatment of ABSSSi caused by MRSA (NCT01593761). CG400549 (40)226, 227, 228, 229 is another FabI inhibitor, derived from the topical biocide triclosan, a broad-spectrum antibiotic used in cleaning and personal care products first launched in the early 1970s.230
The fluoroquinolone WCK-771, which is the arginine salt of S-(–)-nadifloxacin (41), and its pro-drug WCK-2349 (structure not published) are undergoing testing in phase-II trials by Wockhardt Limited (Mumbai, India). Nadifloxacin is a racemic fluoroquinolone launched as a topical antibiotic in Japan in 1993 to treat acne and methicillin-resistant staphylococcal infections.231 Scientists at Wockhardt discovered that the S enantiomer of nadifloxacin, WCK-771 (41), was more active than the racemic mixture and had pharmacokinetic properties amenable for systemic use.231, 232, 233, 234
β-Lactam/β-lactamase inhibitor combinations in phase-II trials
CXL (ceftaroline (23)/avibactam (22; NXL104)) is being developed by AstraZeneca (London, UK) in a phase-II trial for the treatment of MRSA.235 Avibactam (22) is a DBO-type β-lactamase inhibitor described in detail earlier in the phase-III section, whereas ceftaroline fosamil (23) is a cephalosporin approved in 2010 for the treatment of CABP and ABSSSi.236 The CXL combination has activity against Enterobacteriaceae with class A and C β-lactamases and MRSA.133, 237, 238
A combination therapy of imipenem (42), cilastatin (43) and MK-7655 (44) is being developed by Merck (Rahway, NJ, USA) and is being evaluated in phase-II trials for UTI (NCT01505634) and cIAI (NCT01506271). MK-7655 (44) is a DBO β-lactamase inhibitor related to avibactam (22),239 whereas imipenem (42) is a carbapenem first launched in 1987 that needs to be co-administered with the dehydropeptidase inhibitor cilastatin (43) in order to slow down the metabolism of imipenem.240 The imipenem (42) and MK-7655 (44) combination therapy displays in vitro activity against carbapenem-resistant Gram-negative bacteria.241
NP and NP-derived compounds in phase-I trials
BAL30072 (45)242, 243, 244 is a monobactam derivative with an iron-chelating dihydroxypyridone moiety that is being tested by Basilea Pharmaceutica (Basel, Switzerland) in phase-I trials. BAL30072 (45) displays activity against many Gram-negative bacteria242 including P. aeruginosa,245 A. baumannii246, 247 and Burkholderia pseudomallei248 and is rapidly absorbed into bacteria via the essential iron uptake systems.242, 245
Exeporfinium chloride (46; XF-73) is a porphyrin derivative being developed by Destiny Pharma (Brighton, UK) that is being investigated in collaboration with the NIAID in a phase-I trial as an intranasal gel formulation for the nasal decolonization of S. aureus (NCT01592214). XF-73 (46) has successfully completed three phase-I/IIa trials in the United Kingdom249 and has broad-spectrum Gram-positive activity,250, 251, 252, 253, 254 as well as activity against the fungus Candida albicans.255
NVB302 (47) is a semi-synthetic aminoheptylamido derivative256, 257 of the new Type B lantibiotic deoxyactagardine B being developed by Novacta Biosystems Limited (Welwyn Garden City, UK) in collaboration with the Wellcome Trust (London, UK) that has completed a phase-I trial as a treatment for CDI.258 Deoxyactagardine B is produced by Actinoplanes liguriae NCIMB41362 and its biosynthetic cluster has been characterized.259 NVB302 (47) has displayed activity in an in vitro C. difficile gut model.260 Like other related lantibiotics,261 NVB302 (47) exerts its antibacterial activity through binding to the cell wall peptidoglycan precursor lipid II.
S-649266 (GSK-2696266) is a cephem derivative from Shionogi & Co., Ltd (Osaka, Japan) being co-developed with GSK (London, UK) that is in phase-I.262, 263, 264 The structure has not been publically released. 262, 263
Protein/large peptide-derived compounds in phase-I trials
POL7080 is a synthetic cyclic peptide based on protegrin I, which was first isolated from porcine leucocytes.265 Developed by Polyphor Ltd (Basel, Switzerland), POL7080 has successfully completed a phase-I trial.266, 267 POL7080 has potent and selective antimicrobial activity against Gram-negative bacteria including P. aeruginosa and has a novel mode of action through targeting the β-barrel protein LptD (Imp/OstA), which is involved in the outer-membrane biogenesis of LPS.267, 268
Synthetic compounds in phase-I trials
There are two oxazolidinones, LCB01-0371 (48) and MRX-I (49), in phase-I trials. LCB01-0371 (48)269 belongs to LegoChem Biosciences, Inc. (Daejeon, South Korea) and is currently being investigated in one phase-I trial (NCT01842516) and has recently completed another phase-I trial (NCT01554995). MRX-I (49)270 is being developed by MicuRx (Hayward, CA, USA, and Shanghai, China) and completed a phase-I trial in April 2012.271
SMT-19969 is a synthetic compound272 from Summit Corporation PLC (Oxford, UK) that is being developed for the treatment of CDI in collaboration with the Wellcome Trust (London, UK). It recently completed a phase-I study273 that showed SMT 19969 was well tolerated at therapeutically relevant doses and was highly sparing of gut flora with only the clostridia bacterial family being reduced to levels below the limit of detection.273 The Wellcome Trust has awarded Summit an additional Translational Award for further development.273
ACHN-975 is an LpxC (UDP-3-O-(3R)-hydroxymyristoyl)-N-acetylglucosamine deacetylase) inhibitor274 being developed by Achaogen, Inc. (South San Francisco, CA, USA) that has completed one phase-1 trial (NCT01597947) and recently started another phase-I trial (NCT01870245). LpxC is an essential zinc-dependent metalloamidase involved in the biosynthesis of lipid A, the subunit of LPS that anchors the LPS to a phospholipid layer to form the outer membrane of Gram-negative bacteria.275, 276 ACHN-975 has broad-spectrum activity against Gram-negative bacteria including MDR P. aeruginosa, MDR E. coli and Yersinia pestis (the cause of the Black Death plague and a potential biological warfare agent).277
GSK-2140944 is a bacterial type II topoisomerase inhibitor being investigated by GSK (London, UK) in two phase-I clinical trials (NCT01706315 and NCT01615796). There is no further information available about GSK-2140944.264
KPI-10 (50; WQ-3813) is a fluoroquinolone discovered by Wakunaga Pharmaceutical Co., Ltd. (Osaka, Japan) being developed by Kalidex Pharmaceuticals, Inc. (Menlo Park, CA, USA). It has completed a phase-I trial.278, 279
Daiichi-Sankyo (Tokyo, Japan) is investigating DS-8587 (51), another fluoroquinolone, in a phase-I trial.280 DS-8587 (51) is less affected by efflux pumps and induces a lower frequency of single-step mutations compared with ciprofloxacin, and has potential as a treatment for A. baumannii infections.281
AM1977X (oral agent) and KRP-AM1977Y (IV agent) are quinolones that are being developed by Kyorin Pharmaceutical Co., Ltd (Tokyo, Japan) and are currently in phase-I trials.282
β-Lactam/β-lactamase inhibitor combinations in phase-I trials
ATM-AVI is a combination283 of aztreonam (24), a monobactam first launched in 1984, and avibactam (22; NXL104), a DBO β-lactamase inhibitor previously discussed in the phase-II and -III sections, being developed by AstraZeneca (London, UK). ATM-AVI was being evaluated in a phase-I trial (NCT01689207) but the study was recently suspended because of poor participant recruitment.
Carbavance™ is a combination of biapenem (52; RPX2003), a carbapenem first launched in Japan in 2001, and RPX7009 (53), a novel boron-containing β-lactamase inhibitor,284 being developed by Rempex Pharmaceuticals (San Diego, CA, USA). Carbavance has completed one phase-I trial (NCT01702649) and is being evaluated in two other phase-I trials (NCT01751269 and NCT01772836). The combination is active against β-lactamase containing Gram-negative bacteria including K. pneumoniae carbapenemase.285
Analysis of Compounds Undergoing Clinical Trials
Numbers of compounds undergoing clinical evaluation and their source derivation
There are a total of 49 compounds and 6 β-lactam/β-lactamase inhibitor combinations currently undergoing clinical trials (Figure 11). There is 1 compound being evaluated in a NDA/MAA (Table 2), 15 compounds in phase-III (Table 2), 20 compounds in phase-II (Table 3) and 13 compounds in phase-I (Table 4), with two β-lactam/β-lactamase inhibitor combinations in each of phase-I, -II and -III (Tables 2, 3, 4). Twenty-five antibiotics are synthetically derived (S), sixteen NP-derived (NP), six protein/mammalian peptide-derived (P) and two compounds are of unknown derivation. The distribution between NP-, P- and S-derived compounds is relatively similar in phase-I and -II, as was observed in 2011.2 The number of synthetic compounds (nine) in phase-III and NDA/MAA has now surpassed the NP-derived compounds (six), which is in contrast to 2011 when the NP-derived compounds dominated the synthetic compounds five to one.2 There are 10 more compounds undergoing phase-III and NDA/MAA evaluation in 2013 compared with 2011 (Figure 12) and this is due to a surge in recent trials starting for both the NP-derived (eravacycline (6), solithromycin (7) and surotomycin (8)) and S-derived compounds (delamanid (10), perchlozone (11), SQ109 (12), finafloxacin (13), delafloxacin (14), avarofloxacin (15), zabofloxacin (16), nemonoxacin (17) and ozenoxacin (18)). It is striking that the number of compounds across phase-I/II/III is relatively constant, compared with the normal ‘pyramid’ seen in other therapeutic areas. This may reflect a low attrition rate for antibiotics progressing through phase-I to -III trials, but is more likely to be representative of the lack of new antibiotics entering the pipeline over the past decade. With only 13 compounds and 2 β-lactam/β-lactamase inhibitor combinations currently in phase-I, the number of compounds in phase-III in 5 years does not look promising.
New antibacterial template analysis
The NP- and P-derived compound derivations are quite diverse but there are only five new antibacterial templates derived from NPs, whereas there are six from protein/mammalian peptide (P) templates (Figure 13). The new NP templates are derived from thiopeptide (LFF-571 (25)/GE2270-A), N-chlorotaurine (auriclosene (26)/N-chlorotaurine), actinonin (GSK1322322 (30)/actinonin), porphyrin (exeporfinium (46)/porphyrin) and type B lantibiotic (NVB302 (47)/deoxyactagardine B). Deoxyactagardine B is the only recently discovered lead compound but is an analog of a previously discovered lantibiotic.260 Although there are no new NP-derived templates currently in late-stage development, the new template NP fidaxomicin (1) was launched in 2011 (Table 1). The newly created subclass of natural occurring protein/mammalian peptide leads introduced into this review accounts for six new antibacterial templates with all of the compounds (brilacidin (31), LTX-109 (32), DPK-060, LL-37 (33), IMX-942, POL7080) derived from or inspired by naturally occurring cationic peptides. NPs have traditionally been the main source of most new antibiotic drug leads and further investment in NP drug discovery may help reinvigorate the antibiotic field.24, 286, 287, 288
Similarly, the new synthetically derived antibacterial templates are diverse: perchlozone (11; thiosemicarbazone), cadazolid (38; oxazolidinone and quinolone chimera), AFN-1252 (39; benzodiazepine), CG400549 (40; triclosan) and SMT-19969 (bibenzo[d]imidazole). The derivation of ACHN-975 has not been published but it is likely to be a new template, whereas the lead for GSK-214094 has not been published.
There are three new β-lactamase inhibitors with two new templates: avibactam (22) and MK-7655 (44) from the DBO class and RPX7009 (53) from the boron class. Both have been classified as synthetically derived but are inspired by the NP clavulanic acid, which was the first β-lactamase inhibitor reported.130, 131
The total number of new templates has risen from 11 in 2011 to 17 in 2013 (Figure 14), which is predominantly due to the increase in protein/peptide (P)-derived cationic antimicrobial peptides undergoing clinical evaluation. Since 2011, three compounds with new antibacterial templates, GSK-2251052, ramoplanin and lotilibcin (Table 5), are not currently being actively pursued.
Conclusion and Future Outlook
These are challenging, but exciting times for antibiotic research. Around 5 years ago the FDA changed the regulatory framework of phase-III clinical trials, which resulted in a re-evaluation of many late-stage clinical programs and the demise of many antibiotic-focused biotech companies. These uncertainties, along with the costs of these large late-stage trials and comparably poor returns, were a contributing factor in the exodus of many large companies from antibiotic research. However, there is now hope on the horizon with the FDA and companies starting to agree on feasible clinical trial designs. There has been an upsurge in recently initiated phase-III trials, and a push for more innovative ways to discover, develop and register new antibiotics. The EU’s EMA has been slightly ahead of the FDA and has publically recognized the need for new antibiotics and the issues holding back antibiotic development. However, the FDA has just released new draft guidelines that address many of these pressing issues.289 Another advance has been the advent of public–private partnerships in the development of TB drugs. A partnership between Tibotec (Beerse, Belgium) and the Global Alliance for TB Drug Development (New York, NY, USA) culminated in the December 2012 approval of bedaquiline (2) for the treatment of TB, which was the first new TB treatment launched for over 40 years. There are six other potential TB drugs in clinical development, delamanid (10; NDA, phase-III), perchlozone (11; complete phase-II/III), SQ109 (12; phase-III), PA-824 (34; phase-II), sutezolid (36) and posizolid (37) and a number of others in pre-clinical development.290 The Wellcome Trust (London, UK) has also been supporting antibiotic research and has been helping to fund the clinical trials of two compounds, NVB302 (47) and SMT-19969, for the treatment of CDIs. The US government organizations, BARDA and NIAID, have provided additional support for clinical development programs.
Although there has been a slow but steady stream of new compounds entering the clinical pipeline, the difficulty of finding a truly novel antibacterial cannot be overstated. As noted in our previous review2 and by others,20, 25, 26, 291 this is especially the case for Gram-negative bacteria where there is a dearth of new antibiotics to treat these bacteria. Other than the quinolones, which already have resistance issues, the only other compounds in development with activity against Gram-negative bacteria are the topically administered N-chlorotaurine mimic auriclosene (26), the systematically administered aminoglycoside plazomicin (28), the peptide deformylase inhibitor GSK1322322 (30), the monobactam-siderophore hybrid BAL30072 (45), the cationic peptide POL7080 and the LpxC inhibitor ACHN-975. Importantly, the six β-lactamase inhibitor/β-lactam combination therapies in clinical trials have activity against Gram-negative bacteria and will significantly bolster the antibiotic armamentarium if approved.
The real and extremely serious threat of totally antibiotic-resistant bacteria is starting to capture the attention of the public and policy makers. Although the challenges of antibiotic drug discovery are great, there is a dedicated group of researchers actively trying to identify the next generation antibiotics to treat these superbugs. It is imperative that we continue to search for new antibacterial drugs through innovative screening methods of both synthetic and NP libraries and undertake rational drug design from the advances afforded by protein crystal structures.
Davies, S. C. Chief Medical Officer Annual Report https://www.gov.uk/government/publications/chief-medical-officer-annual-report-volume-2, (accessed on 27 May 2013)..
Butler, M. S. & Cooper, M. A. Antibiotics in the clinical pipeline in 2011. J. Antibiot. 64, 413–425 (2011).
Berdy, J. Thoughts and facts about antibiotics: where we are now and where we are heading. J. Antibiot. 65, 385–395 (2012).
Hughes, J. M. Preserving the lifesaving power of antimicrobial agents. JAMA 305, 1027–1028 (2011).
Rolain, J. M., Canton, R. & Cornaglia, G. Emergence of antibiotic resistance: need for a new paradigm. Clin. Microbiol. Infec. 18, 615–616 (2012).
Andersson, D. I. & Hughes, D. Evolution of antibiotic resistance at non-lethal drug concentrations. Drug Resist. Updates. 15, 162–172 (2012).
Wellington, E. M. H. et al. The role of the natural environment in the emergence of antibiotic resistance in Gram-negative bacteria. Lancet Infect. Dis. 13, 155–165 (2013).
Rodríguez-Rojas, A., Rodríguez-Beltrán, J., Couce, A. & Blázquez, J. Antibiotics and antibiotic resistance: a bitter fight against evolution. Int. J. Med. Microbiol. 303, 293–297 (2013).
Anonymous. 35 years of resistance. Nat. Rev. Microbiol. 10, 373–373 (2012).
Hawser, S. in Antibiotic Resistance Vol. 211 Handbook of Experimental Pharmacology ed. Coates A. R. M., 31–43 Springer, Berlin Heidelberg, (2012).
Kuti, J. Tribulations of trials for antibacterial drugs: interview with Joseph Kuti. Clin. Invest. 1, 921–924 (2011).
Lawrence, R. S. The Rise of Antibiotic Resistance: Consequences of FDA's Inaction (23 January 2012) http://www.theatlantic.com/health/archive/2012/01/the-rise-of-antibiotic-resistance-consequences-of-fdas-inaction/251754/, (accessed on 27 May 2013).
Grady, D. Deadly Bacteria That Resist Strongest Drugs Are Spreading (5 March 2013) http://www.nytimes.com/2013/03/06/health/deadly-drug-resistant-infections-rise-in-hospitals-report-warns.html, (accessed on 11 June 2013).
Nathan, C. F. Let’s Gang Up on Killer Bugs (9 December 2012) http://www.nytimes.com/2012/12/10/opinion/teaming-up-to-make-new-antibiotics.html (accessed on 27 May 2013).
Cain, C. Rediscovering antibiotics SciBX 5 doi:10.1038/scibx.2012.1198 (2012).
Cooper, M. A. & Shlaes, D. Fix the antibiotics pipeline. Nature 472, 32 (2011).
Laxminarayan, R. & Powers, J. H. Antibacterial R&D incentives. Nat. Rev. Drug Discov. 10, 727–728 (2011).
Spellberg, B., Sharma, P. & Rex, J. H. The critical impact of time discounting on economic incentives to overcome the antibiotic market failure. Nat. Rev. Drug Discov. 11, 168 (2012).
So, A. D. et al. Towards new business models for R&D for novel antibiotics. Drug Resist. Updates 14, 88–94 (2011).
Boucher, H. W. et al. The 10 X '20 Initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin. Infect. Dis. 50, 1081–1083 (2010).
Spellberg, B. Antibiotic Resistance: Promoting Critically Needed Antibiotic Research and Development and Appropriate Use (‘Stewardship’) of these Precious Drugs (2010). http://www.idsociety.org/uploadedFiles/IDSA/Policy_and_Advocacy/Current_Topics_and_Issues/Advancing_Product_Research_and_Development/Antimicrobials/Statements/IDSATestimony%20Final%20with%20references%20060310.pdf (accessed on 15 July 2013).
Boucher, H. W. et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin. Infect. Dis. 48, 1–12 (2009).
O'Shea, R. & Moser, H. E. Physicochemical properties of antibacterial compounds: implications for drug discovery. J. Med. Chem. 51, 2871–2878 (2008).
Silver, L. L. Are natural products still the best source for antibacterial discovery? The bacterial entry factor. Expert Opin. Drug Discov. 3, 487–500 (2008).
Silver, L. L. Challenges of antibacterial discovery. Clin. Microbiol. Rev. 24, 71–109 (2011).
Boucher, H. W. et al. 10 × '20 Progress—Development of new drugs active against Gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin. Infect. Dis. 56, 1685–1694 (2013).
AstraZeneca outlines strategy to return to growth and achieve scientific leadership Press release 21 March 2013 http://www.astrazeneca.com/Media/Press-releases/Article/20130321—astrazeneca-outlines-strategy-return-to-growth-scientific-leadership, (accessed on 27 May 2013).
Shlaes, D. Pfizer Abandons Antibiotic Research! (3 February 2011) http://antibiotics-theperfectstorm.blogspot.com.au/2011/02/pfizer-abandons-antibiotic-research.html, (accessed on 27 May 2013).
Payne, D. J., Gwynn, M. N., Holmes, D. J. & Pompliano, D. L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat. Rev. Drug Discov. 6, 29–40 (2007).
Linezolid, The Merck Manual, http://www.merckmanuals.com/professional/lexicomp/linezolid.html, (accessed on 15 July 2013).
Daptomycin, The Merck Manual, http://www.merckmanuals.com/professional/lexicomp/daptomycin.html, (accessed on 15 July 2013).
Quinupristin and Dalfopristin, The Merck Manual, http://www.merckmanuals.com/professional/lexicomp/quinupristin%20and%20dalfopristin.html, (accessed on 15 July 2013).
Vancomycin, The Merck Manual, http://www.merckmanuals.com/professional/lexicomp/vancomycin.html (accessed on 15 July 2013).
Bhavnani, S. M., Prakhya, A., Hammel, J. P. & Ambrose, P. G. Cost-effectiveness of daptomycin versus vancomycin and gentamicin for patients with methicillin-resistant Staphylococcus aureus bacteremia and/or endocarditis. Clin. Infect. Dis. 49, 691–698 (2009).
Mossialos, E. et al Policies and Incentives for Promoting Innovation in Antibiotic Research (London School of Economics and Political Science, 2009). http://www.euro.who.int/en/what-we-publish/abstracts/policies-and-incentives-for-promoting-innovation-in-antibiotic-research, (accessed on 27 May 2013).
GlaxoSmithKline awarded up to $200 million by U.S. government to develop new antibiotics (Press release 22 May 2013) http://www.gsk.com/media/press-releases/2013/glaxosmithkline-awarded-up-to—200-million-by-u-s—government-to.html, (accessed on 30 May 2013).
Achaogen Awarded Contract Worth up to $64 Million by BARDA for the Development of ACHN-490 (Press release 30 August 2010) http://www.achaogen.com/news/83/52, (accessed on 30 May 2013).
BARDA Awards Contract Worth up to $67 Million for the Development of a Novel Tetraphase Antibiotic (Press release 12 February 2012) http://ir.tphase.com/releasedetail.cfm?ReleaseID=747629, (accessed on 30 May 2013).
Cempra Awarded $58 Million Contract to Develop Antibiotic for Pediatric Use and Biodefense by Biomedical Advanced Research and Development Authority (BARDA) (Press release 28 May 2013) http://investor.cempra.com/releasedetail.cfm?ReleaseID=767526, (accessed on 30 May 2013).
Kirst, H. A. Recent derivatives from smaller classes of fermentation-derived antibacterials. Expert Opin. Ther. Pat. 22, 15–35 (2012).
Shlaes, D. M. & Spellberg, B. Overcoming the challenges to developing new antibiotics. Curr. Opin. Pharmacol. 12, 522–526 (2012).
Moir, D. T., Opperman, T. J., Butler, M. M. & Bowlin, T. L. New classes of antibiotics. Curr. Opin. Pharmacol. 12, 535–544 (2012).
Dawson, M. J. & Scott, R. W. New horizons for host defense peptides and lantibiotics. Curr. Opin. Pharmacol. 12, 545–550 (2012).
Bush, K. Improving known classes of antibiotics: an optimistic approach for the future. Curr. Opin. Pharmacol. 12, 527–534 (2012).
Sutcliffe, J. A. Antibiotics in development targeting protein synthesis. Ann. N. Y. Acad. Sci. 1241, 122–152 (2011).
McAlpine, J. B., Jackson, M., Karwowski, J., Theriault, R. J. & Hochlowski, J. (Abbott Laboratories). Tiacumicin compounds. U.S. Patent 4,918,174 ((1990).
Hochlowski, J. E. et al. Tiacumicins, a novel complex of 18-membered macrolides. II. Isolation and structure determination. J. Antibiot. 40, 575–588 (1987).
Theriault, R. J. et al. Tiacumicins, a novel complex of 18-membered macrolide antibiotics. I. Taxonomy, fermentation and antibacterial activity. J. Antibiot. 40, 567–574 (1987).
Coronelli, C., White, R. J., Lancini, G. C. & Parenti, F. Lipiarmycin, a new antibiotic from Actinoplanes. II. Isolation, chemical, biological, and biochemical characterization. J. Antibiot. 28, 253–259 (1975).
Coronelli, C., Parenti, F., White, R. & Pagani, H. (Gruppo Lepetit S.p.A.). Lipiarmycin and its preparation. US Patent 3,978,211 (1976).
Parenti, F., Pagani, H. & Beretta, G. Lipiarmycin, a new antibiotic from Actinoplanes. I. Description of the producer strain and fermentation studies. J. Antibiot. 28, 247–252 (1975).
Sergio, S., Pirali, G., White, R. & Parenti, F. Lipiarmycin, a new antibiotic from Actinoplanes. III. Mechanism of action. J. Antibiot. 28, 543–549 (1975).
Arnone, A., Nasini, G. & Cavalleri, B. Structure elucidation of the macrocyclic antibiotic lipiarmycin. J. Chem. Soc. Perkin. Trans. 1 1353–1359 (1987).
Cavalleri, B., Arnone, A., Di, M. E., Nasini, G. & Goldstein, B. P. Structure and biological activity of lipiarmycin B. J. Antibiot. 41, 308–315 (1988).
Omura, S. et al. Clostomicins, new antibiotics produced by Micromonospora echinospora subsp. armeniaca subsp. nov. I. Production, isolation, and physicochemical and biological properties. J. Antibiot. 39, 1407–1412 (1986).
Tupin, A., Gualtieri, M., Leonetti, J.-P. & Brodolin, K. The transcription inhibitor lipiarmycin blocks DNA fitting into the RNA polymerase catalytic site. EMBO J. 29, 2527–2537 (2010).
Rodgers, W., Frazier, A. D. & Champney, W. S. Solithromycin Inhibition of Protein Synthesis and Ribosome Biogenesis in Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. Antimicrob. Agents Chemother. 57, 1632–1637 (2013).
Isaksson, J. et al. A synthetic antimicrobial peptidomimetic (LTX 109): stereochemical impact on membrane disruption. J. Med. Chem. 54, 5786–5795 (2011).
Ranall, M. V., Butler, M. S., Blaskovich, M. A. & Cooper, M. A. Resolving biofilm infections: current therapy and drug discovery strategies. Curr. Drug Targets 13, 1375–1385 (2012).
Webb, S. Public-private partnership tackles TB challenges in parallel. Nat. Rev. Drug Discov. 8, 599–600 (2009).
Unique Collaboration Between TB Alliance and Tibotec to Accelerate Tuberculosis Drug Development (TB Alliance News Center, 17 June 2009) http://www.tballiance.org/newscenter/view-brief.php?id=854, (accessed on 15 July 2013).
Andries, K. et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307, 223–227 (2005).
Koul, A. et al. Diarylquinolines target subunit c of mycobacterial ATP synthase. Nat. Chem. Biol. 3, 323–324 (2007).
Haagsma, A. C. et al. Selectivity of TMC207 towards mycobacterial ATP synthase compared with that towards the eukaryotic homologue. Antimicrob. Agents Chemother 53, 1290–1292 (2009).
Zhanel, G. et al. New lipoglycopeptides. Drugs 70, 859–886 (2010).
Malabarba, A. et al. Amides of de-acetylglucosaminyl-deoxy teicoplanin active against highly glycopeptide-resistant enterococci. Synthesis and antibacterial activity. J. Antibiot. 47, 1493–1506 (1994).
Borghi, A. et al. Deacylation of the glycopeptide antibiotic A40926 by Actinoplanes teichomyceticus ATCC 31121. J. Antibiot. 49, 607–609 (1996).
Malabarba, A. & Goldstein, B. P. Origin, structure, and activity in vitro and in vivo of dalbavancin. J. Antimicrob. Chemother 55, ii15–ii20 (2005).
Guskey, M. T. & Tsuji, B. T. A comparative review of the lipoglycopeptides: oritavancin, dalbavancin, and telavancin. Pharmacotherapy 30, 80–94 (2010).
Durata Therapeutics Announces Phase 3 Clinical Trial Results for Dalbavancin in the Treatment of ABSSSI (Press release 11 December 2012) http://www.duratatherapeutics.com/media-center/press-releases?detail=333, (accessed on 23 May 2013).
Durata Therapeutics Announces Preliminary, Topline Phase 3 Clinical Trial Results for Dalbavancin in the Treatment of ABSSSI (Press release 25 February 2013) http://www.duratatherapeutics.com/media-center/press-releases?detail=364, (accessed on 23 May 2013).
Cooper, R. D. G. et al. Reductive alkylation of glycopeptide antibiotics: synthesis and antibacterial activity. J. Antibiot. 49, 575–581 (1996).
Bouza, E. & Burillo, A. Oritavancin: a novel lipoglycopeptide active against Gram-positive pathogens including multiresistant strains. Int. J. Antimicrob. Agents 36, 401–407 (2010).
The Medicines Company Announces Positive Trial Results for Oritavancin in the Treatment of Acute Bacterial Skin and Skin Structure Infections (ABSSSI) (Press release 20 December 2012) http://www.themedicinescompany.com/, (accessed on 23 May 2013).
Wang, Y., Castaner, R., Bolos, J. & Estivill, C. Amadacycline: tetracycline antibiotic. Drugs Future 34, 11–15 (2009).
Noel, G. J., Draper, M. P., Hait, H., Tanaka, S. K. & Arbeit, R. D. A randomized, evaluator-blind, phase 2 study comparing the safety and efficacy of omadacycline to those of linezolid for treatment of complicated skin and skin structure infections. Antimicrob. Agents Chemother. 56, 5650–5654 (2012).
Paratek Pharmaceuticals Files Registration Statement for Proposed Initial Public Offering (Press release 27 September 2012) http://www.paratekpharm.com/press/092712_Paratek_S-1_Initial_Filing_Release.pdf, (accessed on 11 June 2013).
Xiao, X.-Y. et al. Fluorocyclines. 1. 7-Fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline: a potent, broad spectrum antibacterial agent. J. Med. Chem. 55, 597–605 (2012).
Clark, R. B. et al. Fluorocyclines. 2. Optimization of the C-9 side-chain for antibacterial activity and oral efficacy. J. Med. Chem. 55, 606–622 (2012).
Ronn, M. et al. Process R&D of eravacycline: the first fully synthetic fluorocycline in clinical development. Org. Process Res. Dev. 17, 838–845 (2013).
Grossman, T. H. et al. Target- and resistance-based mechanistic studies with TP-434, a novel fluorocycline antibiotic. Antimicrob. Agents Chemother. 56, 2559–2564 (2012).
Duffield, J., Shue, Y.-K., Ichikawa, Y. & Hwang, C.-K. (Optimer Pharmaceuticals, Inc.). Antibacterial agents. US Patent 8,343,936 (2013).
Golparian, D., Fernandes, P., Ohnishi, M., Jensen, J. S. & Unemo, M. In vitro activity of the new fluoroketolide solithromycin (CEM-101) against a large collection of clinical neisseria gonorrhoeae isolates and international reference strains, including those with high-level antimicrobial resistance: potential treatment option for gonorrhea? Antimicrob. Agents Chemother. 56, 2739–2742 (2012).
Putnam, S. D., Sader, H. S., Farrell, D. J., Biedenbach, D. J. & Castanheira, M. Antimicrobial characterisation of solithromycin (CEM-101), a novel fluoroketolide: activity against staphylococci and enterococci. Int. J. Antimicrob. Agents 37, 39–45 (2011).
Farrell, D. J., Castanheira, M., Sader, H. S. & Jones, R. N. The in vitro evaluation of solithromycin (CEM-101) against pathogens isolated in the United States and Europe (2009). J. Infect. 61, 476–483 (2010).
Bertrand, D., Bertrand, S., Neveu, E. & Fernandes, P. Molecular characterization of off-target activities of telithromycin: a potential role for nicotinic acetylcholine receptors. Antimicrob. Agents Chemother. 54, 5399–5402 (2010).
Pearson, A. L., Metcalf, C. A. III & Li, J. (Cubist Pharmaceuticals, Inc.). Novel lipopeptide antibacterial agents for the treatment of Gram positive infections. US Patent 2010/184649 (2012).
Snydman, D. R., Jacobus, N. V. & McDermott, L. A. Activity of a novel cyclic lipopeptide, CB-183,315, against resistant clostridium difficile and other gram-positive aerobic and anaerobic intestinal pathogens. Antimicrob. Agents Chemother. 56, 3448–3452 (2012).
Mascio, C. T. M. et al. In vitro and in vivo characterization of CB-183,315, a novel lipopeptide antibiotic for treatment of Clostridium difficile. Antimicrob. Agents Chemother. 56, 5023–5030 (2012).
Citron, D. M., Tyrrell, K. L., Merriam, C. V. & Goldstein, E. J. C. In vitro activities of CB-183,315, vancomycin, and metronidazole against 556 strains of Clostridium difficile, 445 Other intestinal anaerobes, and 56 enterobacteriaceae species. Antimicrob. Agents Chemother. 56, 1613–1615 (2012).
Im, W. B. et al. Discovery of torezolid as a novel 5-hydroxymethyl-oxazolidinone antibacterial agent. Eur. J. Med. Chem. 46, 1027–1039 (2011).
Kanafani, Z. A. & Corey, G. R. Tedizolid (TR-701): a new oxazolidinone with enhanced potency. Expert Opin. Invest. Drugs 21, 515–522 (2012).
Shaw, K. J. & Barbachyn, M. R. The oxazolidinones: past, present, and future. Ann. N. Y. Acad. Sci. 1241, 48–70 (2011).
Prokocimer, P., De Anda, C., Fang, E., Mehra, P. & Das, A. Tedizolid phosphate vs linezolid for treatment of acute bacterial skin and skin structure infections: the establish-1 randomized trial. JAMA 309, 559–569 (2013).
Rodríguez-Avial, I. et al. In vitro activity of tedizolid (TR-700) against linezolid-resistant staphylococci. J. Antimicrob. Chemother. 67, 167–169 (2012).
Locke, J. B., Hilgers, M. & Shaw, K. J. Novel ribosomal mutations in Staphylococcus aureus strains identified through selection with the oxazolidinones linezolid and torezolid (TR-700). Antimicrob. Agents Chemother. 53, 5265–5274 (2009).
Gler, M. T. et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N. Engl. J. Med. 366, 2151–2160 (2012).
Sasaki, H. et al. Synthesis and antituberculosis activity of a novel series of optically active 6-nitro-2,3-dihydroimidazo[2,1-b]oxazoles. J. Med. Chem. 49, 7854–7860 (2006).
Matsumoto, M. et al. OPC-67683, a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice. PLoS Med. 3, 2131–2144 (2006).
Ashtekar, D. R. et al. In vitro and in vivo activities of the nitroimidazole CGI 17341 against Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 37, 183–186 (1993).
Gurumurthy, M. et al. Substrate specificity of the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis responsible for the bioreductive activation of bicyclic nitroimidazoles. FEBS J. 279, 113–125 (2012).
Smolentsev, A. I., Lavrenova, L. G., Elokhina, V. N., Nakhmanovich, A. S. & Larina, L. I. Crystal structures of pyridine-4-aldehyde thiosemicarbazone perchlorate and trifluoromethane sulfonate. J. Struct. Chem. 50, 500–504 (2009).
Gushchin, A. S. et al(JSC Pharmasyntez). Tuberculosis drug based on 4-thioureido-iminomethylpyridinium perchlorate: method of preparation and treatment. US Patent 2013/052265 (2013).
Grunberg, E. & Leiwant, B. Antituberculous activity in vivo of nicotinaldehyde thiosemicarbazone and its isomers. Proc. Soc. Exp. Biol. Med. 77, 47–50 (1951).
Fox, H. H. Synthetic tuberculostats. III. Isonicotinaldehyde thiosemicarbazone and some related compounds. J. Org. Chem. 17, 555–562 (1952).
Maxwell Biotech Venture Fund’s Portfolio Company, Infectex, Enrolls First Multi-Drug Resistant Tuberculosis (MDR-TB) Patients in Pivotal Clinical Trial of SQ109, Licensed from Sequella (Press release 19 December 2012) http://www.sequella.com/docs/Sequella_Infectex_Release_19Dec2012.pdf, (accessed on 24 May 2013).
Lee, R. E. et al. Combinatorial lead optimization of [1,2]-diamines based on ethambutol as potential antituberculosis preclinical candidates. J. Comb. Chem. 5, 172–187 (2003).
Tahlan, K. et al. SQ109 Targets MmpL3, a membrane transporter of trehalose monomycolate involved in mycolic acid donation to the cell wall core of Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 56, 1797–1809 (2012).
Lin, F.-Y. et al. Head-to-head prenyl tranferases: anti-infective drug targets. J. Med. Chem. 55, 4367–4372 (2012).
Drlica, K. et al. Quinolones: action and resistance updated. Curr. Top. Med. Chem. 9, 981–998 (2009).
MerLion Announces Initiation of a Phase III Clinical Programme to Evaluate Finafloxacin for the Treatment of Acute Otitis Media (Press Release 18 April 2012) http://www.merlionpharma.com/, (accessed on 11 April 2013).
MerLion Pharmaceuticals Announces Initiation of first Phase II Clinical Study with Finafloxacin in Patients with Complicated Urinary Tract Infections (Press release 11 December 2012) http://www.merlionpharma.com/ (accessed on 11 April 2013).
Wagenlehner, F. M. E. et al. Urinary pharmacokinetics and bactericidal activity of finafloxacin (200 and 800 mg) in healthy volunteers receiving a single oral dose. Chemotherapy 57, 97–107 (2011).
Patel, H. et al. Human pharmacokinetics and safety profile of finafloxacin, a new fluoroquinolone antibiotic, in healthy volunteers. Antimicrob. Agents Chemother. 55, 4386–4393 (2011).
Stubbings, W. et al. In vitro spectrum of activity of finafloxacin, a novel, pH-activated fluoroquinolone, under standard and acidic conditions. Antimicrob. Agents Chemother. 55, 4394–4397 (2011).
Dalhoff, A., Stubbings, W. & Schubert, S. Comparative in vitro activities of the novel antibacterial finafloxacin against selected Gram-positive and Gram-negative bacteria tested in Mueller-Hinton broth and synthetic urine. Antimicrob. Agents Chemother. 55, 1814–1818 (2011).
Higgins, P. G., Stubbings, W., Wisplinghoff, H. & Seifert, H. Activity of the investigational fluoroquinolone finafloxacin against ciprofloxacin-sensitive and -resistant Acinetobacter baumannii isolates. Antimicrob. Agents Chemother. 54, 1613–1615 (2010).
Emrich, N.-C., Heisig, A., Stubbings, W., Labischinski, H. & Heisig, P. Antibacterial activity of finafloxacin under different pH conditions against isogenic strains of Escherichia coli expressing combinations of defined mechanisms of fluoroquinolone resistance. J. Antimicrob. Chemother 65, 2530–2533 (2010).
Dalhoff, A., Schubert, S. & Ullmann, U. Effect of pH on the in vitro activity of and propensity for emergence of resistance to fluoroquinolones, macrolides, and a ketolide. Infection 33, 36–43 (2005).
Lemaire, S., Tulkens, P. M. & Van Bambeke, F. Contrasting effects of acidic pH on the extracellular and intracellular activities of the anti-Gram-positive fluoroquinolones moxifloxacin and delafloxacin against Staphylococcus aureus. Antimicrob. Agents Chemother. 55, 649–658 (2011).
Morrow, B. J. et al. In vitro antibacterial activities of JNJ-Q2, a new broad-spectrum fluoroquinolone. Antimicrob. Agents Chemother. 54, 1955–1964 (2010).
Morrow, B. J. et al. Antistaphylococcal activities of the new fluoroquinolone JNJ-Q2. Antimicrob. Agents Chemother. 55, 5512–5521 (2011).
Park, H.-S. et al. In vitro and in vivo antibacterial activities of DW-224a, a new fluoronaphthyridone. Antimicrob. Agents Chemother. 50, 2261–2264 (2006).
Jones, R. N., Biedenbach, D. J., Ambrose, P. G. & Wikler, M. A. Zabofloxacin (DW-224a) activity against Neisseria gonorrhoeae including quinolone-resistant strains. Diagn. Microbiol. Infect. Dis. 62, 110–112 (2008).
Park, H. S., Jung, S. J., Kwak, J.-H., Choi, D.-R. & Choi, E.-C. DNA gyrase and topoisomerase IV are dual targets of zabofloxacin in Streptococcus pneumoniae. Int. J. Antimicrob. Agents 36, 97–98 (2010).
Hsu, M.-S. et al. In vitro susceptibilities of clinical isolates of ertapenem-non-susceptible Enterobacteriaceae to nemonoxacin, tigecycline, fosfomycin and other antimicrobial agents. Int. J. Antimicrob. Agents 37, 276–278 (2011).
Lauderdale, T.-L., Shiau, Y.-R., Lai, J.-F., Chen, H.-C. & King, C.-H. R. Comparative in vitro activities of nemonoxacin (TG-873870), a novel nonfluorinated quinolone, and other quinolones against clinical isolates. Antimicrob. Agents Chemother. 54, 1338–1342 (2010).
Maruho Co Development pipeline as of 30 June 2012 http://www.maruho.co.jp/english/randd/pipeline.html, (accessed on 31 May 2013).
Yamakawa, T., Mitsuyama, J. & Hayashi, K. In vitro and in vivo antibacterial activity of T-3912, a novel non-fluorinated topical quinolone. J. Antimicrob. Chemother. 49, 455–465 (2002).
Brown, A. G. et al. Naturally-occurring β-lactamase inhibitors with antibacterial activity. J. Antibiot. 29, 668–669 (1976).
Howarth, T. T., Brown, A. G. & King, T. J. Clavulanic acid, a novel β-lactam isolated from Streptomyces clavuligerus; X-ray crystal structure analysis. J. Chem. Soc. Chem. Commun. 266–267 (1976).
Reading, C. & Cole, M. Clavulanic acid: a beta-lactamase-inhibiting beta-lactam from Streptomyces clavuligerus. Antimicrob. Agents Chemother. 11, 852–857 (1977).
Shlaes, D. M. New β-lactam–β-lactamase inhibitor combinations in clinical development. Ann. N. Y. Acad. Sci. 1277, 105–114 (2013).
Coleman, K. Diazabicyclooctanes (DBOs): a potent new class of non-β-lactam β-lactamase inhibitors. Curr. Opin. Microbiol. 14, 550–555 (2011).
Toda, A. et al. Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporins: discovery of FR264205. Bioorg. Med. Chem. Lett. 18, 4849–4852 (2008).
Takeda, S., Nakai, T., Wakai, Y., Ikeda, F. & Hatano, K. In vitro and in vivo activities of a new cephalosporin, FR264205, against Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 51, 826–830 (2007).
Takeda, S., Ishii, Y., Hatano, K., Tateda, K. & Yamaguchi, K. Stability of FR264205 against AmpC β-lactamase of Pseudomonas aeruginosa. Int. J. Antimicrob. Agents 30, 443–445 (2007).
Micetich, R. G. et al. Synthesis and β-lactamase inhibitory properties of 2β-[(1,2,3-triazol-1-yl)methyl]-2α-methylpenam-3α-carboxylic acid 1,1-dioxide and related triazolyl derivatives. J. Med. Chem. 30, 1469–1474 (1987).
Gin, A. et al. Piperacillin–tazobactam: a β-lactam/β-lactamase inhibitor combination. Expert Rev. Anti Infect. Ther. 5, 365–383 (2007).
Zhanel, G. et al. Ceftazidime-Avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Drugs 73, 159–177 (2013).
Richards, D. M. & Brogden, R. N. Ceftazidime. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs 29, 105–161 (1985).
Bonnefoy, A. et al. In vitro activity of AVE1330A, an innovative broad-spectrum non-β-lactam β-lactamase inhibitor. J. Antimicrob. Chemother. 54, 410–417 (2004).
Stachyra, T. et al. Mechanistic studies of the inactivation of TEM-1 and P99 by NXL104, a novel non-β-lactam β-lactamase inhibitor. Antimicrob. Agents Chemother. 54, 5132–5138 (2010).
Ehmann, D. E. et al. Avibactam is a covalent, reversible, non–β-lactam β-lactamase inhibitor. Proc. Natl Acad. Sci. USA 109, 11663–11668 (2012).
Citron, D. M., Tyrrell, K. L., Merriam, C. V. & Goldstein, E. J. C. Comparative in vitro activities of LFF571 against Clostridium difficile and 630 other intestinal strains of aerobic and anaerobic bacteria. Antimicrob. Agents Chemother. 56, 2493–2503 (2012).
Ting, L. S. L. et al. A first-in-human, randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study to assess the safety and tolerability of LFF571 in healthy volunteers. Antimicrob. Agents Chemother. 56, 5946–5951 (2012).
LaMarche, M. J. et al. Discovery of LFF571: an investigational agent for Clostridium difficile infection. J. Med. Chem. 55, 2376–2387 (2012).
Leeds, J. A., Sachdeva, M., Mullin, S., Dzink-Fox, J. & LaMarche, M. J. Mechanism of action of and mechanism of reduced susceptibility to the novel anti-clostridium difficile compound LFF571. Antimicrob. Agents Chemother. 56, 4463–4465 (2012).
Galderma and NovaBay Enroll First Patients in Phase 2b Clinical Study of NVC-422 for Impetigo (Press release 24 September 2012) http://www.galderma.com/, (accessed on 26 April 2013).
Shiau, T. P. et al. Stieglitz rearrangement of N,N-dichloro-β,β-disubstituted taurines under mild aqueous conditions. Bioorg. Med. Chem. Lett. 19, 1110–1114 (2009).
Francavilla, C. et al. Quaternary ammonium N,N-dichloroamines as topical, antimicrobial agents. Bioorg. Med. Chem. Lett. 19, 2731–2734 (2009).
Wang, L., Khosrovi, B. & Najafi, R. N-Chloro-2,2-dimethyltaurines: a new class of remarkably stable N-chlorotaurines. Tetrahedron Lett. 49, 2193–2195 (2008).
Gottardi, W., Debabov, D. & Nagl, M. N-Chloramines, a promising class of well-tolerated topical anti-infectives. Antimicrob. Agents Chemother. 57, 1107–1114 (2013).
Kim, O., Assefa, H. & Honeyman, L. (Paratek Pharmaceuticals). Substituted tetracycline compounds. US Patent 8,318,706 (2012).
Statement on a nonproprietary name adopted by the USAN council (ZZ-27) Sarecycline (26 December 2012) http://www.ama-assn.org/resources/doc/usan/sarecycline.pdf, (accessed on 30 May 2013).
Warner Chilcott, PLC Form 10-Q (Quarterly Report), (Filed 10 May 2013) http://files.shareholder.com/downloads/WCRX/2106704214x0xS1193125-13-212754/1323854/filing.pdf, (accessed on 30 May 2013).
Novak, R. & Shlaes, D. M. The pleuromutilin antibiotics: a new class for human use. Curr. Opin. Invest. Drugs 11, 182–191 (2010).
Novak, R. Are pleuromutilin antibiotics finally fit for human use? Ann. N. Y. Acad. Sci. 1241, 71–81 (2011).
Prince, W. T. et al. Phase II clinical study of BC-3781, a pleuromutilin antibiotic, in treatment of patients with acute bacterial skin and skin structure infections. Antimicrob. Agents Chemother. 57, 2087–2094 (2013).
Sader, H. S. et al. Antimicrobial activity of the novel pleuromutilin antibiotic BC-3781 against organisms responsible for community-acquired respiratory tract infections (CARTIs). J. Antimicrob. Chemother. 67, 1170–1175 (2012).
Sader, H. S., Biedenbach, D. J., Paukner, S., Ivezic-Schoenfeld, Z. & Jones, R. N. Antimicrobial activity of the investigational pleuromutilin compound BC-3781 tested against Gram-positive organisms commonly associated with acute bacterial skin and skin structure infections. Antimicrob. Agents Chemother. 56, 1619–1623 (2012).
Aggen, J. B. et al. Synthesis and spectrum of the neoglycoside ACHN-490. Antimicrob. Agents Chemother. 54, 4636–4642 (2010).
Weinstein, M. J. et al. Antibiotic 6640, a new Micromonospora-produced aminoglycoside antibiotic. J. Antibiot. 23, 551–554 (1970).
Reimann, H. et al. Structure of sisomicin, a novel unsaturated aminocyclitol antibiotic from Micromonospora inyoensis. J. Org. Chem. 39, 1451–1457 (1974).
Tenover, F. C. et al. Activity of ACHN-490 against meticillin-resistant Staphylococcus aureus (MRSA) isolates from patients in US hospitals. Int. J. Antimicrob. Agents 38, 352–354 (2011).
Galani, I. et al. Activity of plazomicin (ACHN-490) against MDR clinical isolates of Klebsiella pneumoniae, Escherichia coli, and Enterobacter spp. from Athens, Greece. J. Chemother. 24, 191–194 (2012).
Landman, D. et al. Antimicrobial activity of a novel aminoglycoside, ACHN-490, against Acinetobacter baumannii and Pseudomonas aeruginosa from New York City. J Antimicrob. Chemother. 66, 332–334 (2011).
Zhanel, G. G. et al. Comparison of the next-generation aminoglycoside plazomicin to gentamicin, tobramycin and amikacin. Expert Rev. Anti Infect. Ther. 10, 459–473 (2012).
O’Dwyer, K. et al. Comparative analysis of the antibacterial activity of a novel peptide deformylase inhibitor, GSK1322322. Antimicrob. Agents Chemother. 57, 2333–2342 (2013).
Sharma, A., Khuller, G. K. & Sharma, S. Peptide deformylase—a promising therapeutic target for tuberculosis and antibacterial drug discovery. Expert Opin.Ther. Targets. 13, 753–765 (2009).
Leeds, J. A. & Dean, C. R. Peptide deformylase as an antibacterial target: a critical assessment. Curr. Opin. Pharmacol. 6, 445–452 (2006).
Azoulay-Dupuis, E., Mohler, J. & Bedos, J. P. Efficacy of BB-83698, a novel peptide deformylase inhibitor, in a mouse model of Pneumococcal Pneumonia. Antimicrob. Agents Chemother. 48, 80–85 (2004).
Osborne, C. S. et al. In vivo characterization of the peptide deformylase inhibitor LBM415 in murine infection models. Antimicrob. Agents Chemother. 53, 3777–3781 (2009).
Waites, K. B., Reddy, N. B., Crabb, D. M. & Duffy, L. B. Comparative in vitro activities of investigational peptide deformylase inhibitor NVP LBM-415 and other agents against human mycoplasmas and ureaplasmas. Antimicrob. Agents Chemother. 49, 2541–2542 (2005).
Gordon, J. J., Kelly, B. K. & Miller, G. A. Actinonin: an antibiotic substance produced by an actinomycete. Nature 195, 701–702 (1962).
Gordon, J. J. et al. Studies concerning the antibiotic actinonin. Part I. The constitution of actinonin. A natural hydroxamic acid with antibiotic activity. J. Chem. Soc. Perkin Trans. 1 819–825 (1975).
Chen, D. Z. et al. Actinonin, a naturally occurring antibacterial agent, is a potent deformylase inhibitor. Biochemistry 39, 1256–1262 (2000).
Shlaes, D. IDSA Update on Antibiotic Development - Hope or Stagnation? (Published 22 April 2013) http://antibiotics-theperfectstorm.blogspot.com.au/2013/04/idsa-update-on-antibiotic-development.html, (accessed on 24 May 2013).
Choi, S. et al. De novo design and in vivo activity of conformationally restrained antimicrobial arylamide foldamers. Proc. Natl Acad. Sci. USA 106, 6968–6973 (2009).
Tew, G. N., Scott, R. W., Klein, M. L. & DeGrado, W. F. De Novo design of antimicrobial polymers, foldamers, and small molecules: from discovery to practical applications. Acc. Chem. Res. 43, 30–39 (2010).
Degrado, W. F. et al(Polymedix, Inc.). Synthetic Mimetics Of Host Defense And Uses Thereof. US Patent 8,278,309 (2012).
Ryge, T. S., Frimodt-Moller, N. & Hansen, P. R. Antimicrobial activities of twenty lysine-peptoid hybrids against clinically relevant bacteria and fungi. Chemotherapy 54, 152–156 (2008).
Saravolatz, L. D. et al. In vitro activities of LTX-109, a synthetic antimicrobial peptide, against methicillin-resistant, vancomycin-intermediate, vancomycin-resistant, daptomycin-nonsusceptible, and linezolid-nonsusceptible Staphylococcus aureus. Antimicrob. Agents Chemother. 56, 4478–4482 (2012).
Mercer, D. K. & O’Neil, D. A. Peptides as the next generation of anti-infectives. Future Med. Chem. 5, 315–337 (2013).
Nordahl, E. A., Rydengård, V., Mörgelin, M. & Schmidtchen, A. Domain 5 of high molecular weight kininogen is antibacterial. J. Biol. Chem. 280, 34832–34839 (2005).
Schmidtchen, A. & Malmsten, M. (Dermagen AB). Use of antimicrobial peptides with heparin binding activity. EP Patent 1,625,155 (2012).
Pergamum announces last visit of last patient in a Phase I/II trial of a potential new treatment for hard-to-heal wounds (Press release 19 April 2013) http://www.pergamum.com/blog/pergamum-announces-last-visit-of-last-patient-in-a-phase-iii-trial-of-a-potential-new-treatment-for-hard-to-heal-wounds/, (accessed on 24 May 2013).
Larrick, J. W. et al. Human CAP18: a novel antimicrobial lipopolysaccharide-binding protein. Infect. Immun. 63, 1291–1297 (1995).
Vandamme, D., Landuyt, B., Luyten, W. & Schoofs, L. A comprehensive summary of LL-37, the factotum human cathelicidin peptide. Cell. Immunol. 280, 22–35 (2012).
Turner, J., Cho, Y., Dinh, N.-N., Waring, A. J. & Lehrer, R. I. Activities of LL-37, a cathelin-associated antimicrobial peptide of human neutrophils. Antimicrob. Agents Chemother. 42, 2206–2214 (1998).
Oren, Z., Lerman, J. C., Gudmundsson, G. H., Agerberth, B. & Shai, Y. Structure and organization of the human antimicrobial peptide LL-37 in phospholipid membranes: relevance to the molecular basis for its non-cell-selective activity. Biochem. J. 341, 501–513 (1999).
Kanthawong, S. et al. Antimicrobial activities of LL-37 and its truncated variants against Burkholderia thailandensis. Int. J. Antimicrob. Agents 36, 447–452 (2010).
Falla, T. J., Karunaratne, D. N. & Hancock, R. E. W. Mode of action of the antimicrobial peptide indolicidin. J. Biol. Chem. 271, 19298–19303 (1996).
Scott, M. G. et al. An anti-infective peptide that selectively modulates the innate immune response. Nat. Biotechnol. 25, 465–472 (2007).
Yu, H. B. et al. Sequestosome-1/p62 is the key intracellular target of innate defense regulator peptide. J. Biol. Chem. 284, 36007–36011 (2009).
Hancock, R. E. W., Nijnik, A. & Philpott, D. J. Modulating immunity as a therapy for bacterial infections. Nat. Rev. Microbiol. 10, 243–254 (2012).
Inimex Pharmaceuticals Technology Overview & Status, http://www.inimex-ivr.com/prod_tech_profile.html, (accessed on 31 May 2013).
Stover, C. K. et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 405, 962–966 (2000).
Singh, R. et al. PA-824 Kills nonreplicating Mycobacterium tuberculosis by intracellular no release. Science 322, 1392–1395 (2008).
Manjunatha, U., Boshoff, H. I. & Barry, C. E. The mechanism of action of PA-824: Novel insights from transcriptional profiling. Commun. Integr. Biol. 2, 215–218 (2009).
Michalska, K., Karpiuk, I., Król, M. & Tyski, S. Recent development of potent analogues of oxazolidinone antibacterial agents. Bioorg. Med. Chem. 21, 577–591 (2013).
Skripkin, E. et al. Rχ-01, a new family of oxazolidinones that overcome ribosome-based linezolid resistance. Antimicrob. Agents Chemother. 52, 3550–3557 (2008).
Zhou, J. et al. Design at the atomic level: design of biaryloxazolidinones as potent orally active antibiotics. Bioorg. Med. Chem. Lett. 18, 6175–6178 (2008).
Lemaire, S. et al. Cellular pharmacodynamics of the novel biaryloxazolidinone radezolid: Studies with infected phagocytic and nonphagocytic cells, using Staphylococcus aureus, Staphylococcus epidermidis, Listeria monocytogenes, and Legionella pneumophila. Antimicrob. Agents Chemother. 54, 2549–2559 (2010).
Lemaire, S., Tulkens, P. M. & Van, B. F. Cellular pharmacokinetics of the novel biaryloxazolidinone radezolid in phagocytic cells: studies with macrophages and polymorphonuclear neutrophils. Antimicrob. Agents Chemother. 54, 2540–2548 (2010).
Lawrence, L., Danese, P., DeVito, J., Franceschi, F. & Sutcliffe, J. In vitro activities of the Rx-01 oxazolidinones against hospital and community pathogens. Antimicrob. Agents Chemother. 52, 1653–1662 (2008).
Zhou, J. et al. Design at the atomic level: generation of novel hybrid biaryloxazolidinones as promising new antibiotics. Bioorg. Med. Chem. Lett. 18, 6179–6183 (2008).
Barbachyn, M. R. et al. Identification of a novel oxazolidinone (U-100480) with potent antimycobacterial activity. J. Med. Chem. 39, 680–685 (1996).
Williams, K. N. et al. Promising antituberculosis activity of the oxazolidinone PNU-100480 relative to that of linezolid in a murine model. Antimicrob. Agents Chemother. 53, 1314–1319 (2009).
Alffenaar, J. W. C. et al. Susceptibility of clinical Mycobacterium tuberculosis isolates to a potentially less toxic derivate of linezolid, PNU-100480. Antimicrob. Agents Chemother. 55, 1287–1289 (2011).
Wallis, R. S. et al. Pharmacokinetics and whole-blood bactericidal activity against Mycobacterium tuberculosis of single doses of PNU-100480 in healthy volunteers. J. Infect. Dis. 202, 745–751 (2010).
Wallis, R. S. et al. Biomarker-assisted dose selection for safety and efficacy in early development of PNU-100480 for tuberculosis. Antimicrob. Agents Chemother. 55, 567–574 (2011).
Wookey, A. et al. AZD2563, a novel oxazolidinone: definition of antibacterial spectrum, assessment of bactericidal potential and the impact of miscellaneous factors on activity in vitro. Clin. Microbiol. Infec. 10, 247–254 (2004).
Gravestock, M. B. et al. New classes of antibacterial oxazolidinones with C-5, methylene O-Linked heterocyclic side chains. Bioorg. Med. Chem. Lett. 13, 4179–4186 (2003).
Kaveri, D., Melnick, D. A. & Radha, S (AstraZeneca, AB). Compound for the treatment of tuberculosis. US Patent 2012/035219 (2012).
Actelion’s novel antibiotic cadazolid to move into Phase III clinical development in patients suffering from Clostridium difficile associated diarrhea (Press release 21 December 2012) http://www1.actelion.com/en/investors/media-releases/index.page?newsId=1666815, (accessed on 18 April 2013).
Locher, H. H. et al Cadazolid, a Novel Quinolonyl-Oxazolidinone Antibiotic: Mode of Action and Effect on Clostridium difficile Toxin and Spore Formation 52nd ICAAC Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Poster C1–1347 San Francisco, CA, USA.
Rashid, M.-U., Lozano, H. M., Weintraub, A. & Nord, C. E. In vitro activity of cadazolid against Clostridium difficile strains isolated from primary and recurrent infections in Stockholm, Sweden. Anaerobe 20, 32–35 (2013).
Parsons, J. B. et al. Perturbation of Staphylococcus aureus gene expression by the enoyl-acyl carrier protein reductase inhibitor AFN-1252. Antimicrob. Agents Chemother. 57, 2182–2190 (2013).
Kaplan, N. et al. Mode of action, in vitro activity, and in vivo efficacy of AFN-1252, a selective antistaphylococcal FabI inhibitor. Antimicrob. Agents Chemother. 56, 5865–5874 (2012).
Lu, H. & Tonge, P. J. Inhibitors of FabI, an enzyme drug target in the bacterial fatty acid biosynthesis pathway. Acc. Chem. Res. 41, 11–20 (2008).
Gerusz, V. in Annu. Rep. Med. Chem. Vol. 45 ed. John E. M., 295–311 Academic Press, (2010).
Payne, D. J. et al. Discovery of a novel and potent class of FabI-directed antibacterial agents. Antimicrob. Agents Chemother. 46, 3118–3124 (2002).
Karlowsky, J. A. et al. In vitro activity of API-1252, a novel FabI inhibitor, against clinical isolates of Staphylococcus aureus and Staphylococcus epidermidis. Antimicrob. Agents Chemother. 51, 1580–1581 (2007).
Karlowsky, J. A., Kaplan, N., Hafkin, B., Hoban, D. J. & Zhanel, G. G. AFN-1252, a FabI inhibitor, demonstrates a Staphylococcus-specific spectrum of activity. Antimicrob. Agents Chemother. 53, 3544–3548 (2009).
Kim, B.-Y. & Sohn, Y.-T. Solid state of CG-400549, a novel FabI inhibitor: characterization, dissolution, transformation. Arch. Pharm. Res. 34, 775–779 (2011).
Yum, J. H. et al. In vitro activities of CG400549, a novel FabI inhibitor, against recently isolated clinical staphylococcal strains in Korea. Antimicrob. Agents Chemother. 51, 2591–2593 (2007).
Park, H. S. et al. Antistaphylococcal activities of CG400549, a new bacterial enoyl-acyl carrier protein reductase (FabI) inhibitor. J. Antimicrob. Chemother. 60, 568–574 (2007).
Bogdanovich, T. et al. Antistaphylococcal activity of CG400549, a new experimental FabI inhibitor, compared with that of other agents. Antimicrob. Agents Chemother. 51, 4191–4195 (2007).
Schweizer, H. P. Triclosan: a widely used biocide and its link to antibiotics. FEMS Microbiol. Lett. 202, 1–7 (2001).
Jacobs, M. R. & Appelbaum, P. C. Nadifloxacin: a quinolone for topical treatment of skin infections and potential for systemic use of its active isomer, WCK 771. Expert Opin. Pharmacother. 7, 1957–1966 (2006).
de Souza, N. J. et al. A chiral benzoquinolizine-2-carboxylic acid arginine salt active against vancomycin-resistant Staphylococcus aureus. J. Med. Chem. 48, 5232–5242 (2005).
Al-Lahham, A., De Souza, N. J., Patel, M. & René Reinert, R. Activity of the new quinolones WCK 771, WCK 1152 and WCK 1153 against clinical isolates of Streptococcus pneumoniae and Streptococcus pyogenes. J. Antimicrob. Chemother. 56, 1130–1133 (2005).
Bhagwat, S. S., McGhee, P., Kosowska-Shick, K., Patel, M. V. & Appelbaum, P. C. In vitro activity of the quinolone WCK 771 against recent U.S. hospital and community-acquired Staphylococcus aureus pathogens with various resistance types. Antimicrob. Agents Chemother. 53, 811–813 (2009).
AstraZeneca Development Pipeline as at 31 December 2012 http://www.astrazeneca.com/Research/Our-pipeline-summary, (accessed on 27 May 2013).
Garrison, M. W., Kawamura, N. M. & Wen, M. M. Ceftaroline fosamil: a new cephalosporin active against resistant Gram-positive organisms including MRSA. Expert Rev. Anti. Infect. Ther. 10, 1087–1103 (2012).
Castanheira, M., Sader, H. S., Farrell, D. J., Mendes, R. E. & Jones, R. N. Activity of ceftaroline-avibactam tested against Gram-negative organism populations, including strains expressing one or more β-lactamases and methicillin-resistant Staphylococcus aureus carrying various Staphylococcal cassette chromosome mec types. Antimicrob. Agents Chemother. 56, 4779–4785 (2012).
Sader, H. S., Flamm, R. K. & Jones, R. N. Antimicrobial activity of ceftaroline-avibactam tested against clinical isolates collected from U.S. Medical Centers in 2010-2011. Antimicrob. Agents Chemother. 57, 1982–1988 (2013).
Mangion, I. K., Ruck, R. T., Rivera, N., Huffman, M. A. & Shevlin, M. A concise synthesis of a β-lactamase inhibitor. Org. Lett. 13, 5480–5483 (2011).
Rodloff, A. C., Goldstein, E. J. C. & Torres, A. Two decades of imipenem therapy. J. Antimicrob. Chemother. 58, 916–929 (2006).
Hirsch, E. B. et al. In vitro activity of MK-7655, a novel β-lactamase inhibitor, in combination with imipenem against carbapenem-resistant Gram-negative bacteria. Antimicrob. Agents Chemother. 56, 3753–3757 (2012).
Page, M. G. P., Dantier, C. & Desarbre, E. In vitro properties of BAL30072, a novel siderophore sulfactam with activity against multiresistant Gram-negative bacilli. Antimicrob. Agents Chemother. 54, 2291–2302 (2010).
Mushtaq, S., Warner, M. & Livermore, D. Activity of the siderophore monobactam BAL30072 against multiresistant non-fermenters. J. Antimicrob. Chemother. 65, 266–270 (2010).
Basilea initiates phase I clinical program of its novel antibiotic BAL30072 (Press release 23 November 2010) http://www.basilea.com/News-and-Media/Basilea-initiates-phase-I-clinical-program-of-its-novel-antibiotic-BAL30072/381, (accessed on 28 February 2011).
van Delden, C., Page, M. G. P. & Köhler, T. Involvement of Fe uptake systems and AmpC β-lactamase in susceptibility to the siderophore monosulfactam BAL30072 in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 57, 2095–2102 (2013).
Hofer, B. et al. Combined effects of the siderophore monosulfactam BAL30072 and carbapenems on multidrug-resistant Gram-negative bacilli. J. Antimicrob. Chemother. 68, 1120–1129 (2013).
Higgins, P. G., Stefanik, D., Page, M. G. P., Hackel, M. & Seifert, H. In vitro activity of the siderophore monosulfactam BAL30072 against meropenem-non-susceptible Acinetobacter baumannii. J. Antimicrob. Chemother. 67, 1167–1169 (2012).
Mima, T. et al. In vitro activity of BAL30072 against Burkholderia pseudomallei. Int. J. Antimicrob. Agents 38, 157–159 (2011).
XF-73 (Destiny Pharmaceuticals Website) http://www.destinypharma.com/xf73.shtml, (accessed on 30 May 2013).
Maisch, T., Bosl, C., Szeimies, R. M., Lehn, N. & Abels, C. Photodynamic effects of novel XF porphyrin derivatives on prokaryotic and eukaryotic cells. Antimicrob. Agents Chemother. 49, 1542–1552 (2005).
Farrell, D. J., Robbins, M., Rhys-Williams, W. & Love, W. G. In vitro activity of XF-73, a novel antibacterial agent, against antibiotic-sensitive and -resistant Gram-positive and Gram-negative bacterial species. Int. J. Antimicrob. Agents 35, 531–536 (2010).
Ooi, N. et al. XF-73, a novel antistaphylococcal membrane-active agent with rapid bactericidal activity. J. Antimicrob. Chemother. 64, 735–740 (2009).
Ooi, N. et al. XF-70 and XF-73, novel antibacterial agents active against slow-growing and non-dividing cultures of Staphylococcus aureus including biofilms. J. Antimicrob. Chemother. 65, 72–78 (2010).
Farrell, D. J., Robbins, M., Rhys-Williams, W. & Love, W. G. Investigation of the potential for mutational resistance to XF-73, retapamulin, mupirocin, fusidic acid, daptomycin, and vancomycin in methicillin-resistant Staphylococcus aureus isolates during a 55-passage study. Antimicrob. Agents Chemother. 55, 1177–1181 (2011).
Gonzales, F. P., Felgenträger, A., Bäumler, W. & Maisch, T. Fungicidal photodynamic effect of a twofold positively charged porphyrin against Candida albicans planktonic cells and biofilms. Future Microbiol. 8, 785–797 (2013).
Appleyard, A. N. & Wadman, S. N. (Novacta Biosystems Limited). Formulation comprising a type B lantibiotic. WO2012/007711 (2012).
Wadman, S. N. (Novacta Biosystems Limited). Compounds. US Patent 8,283,371 (2012).
Novacta Biosystems Limited completes Phase I study of NVB302 against C. difficile infection in healthy volunteers (Press release 6 August 2012) http://www.novactabio.com/news.php, (accessed on 30 May 2013).
Boakes, S., Appleyard, A. N., Cortes, J. & Dawson, M. J. Organization of the biosynthetic genes encoding deoxyactagardine B (DAB), a new lantibiotic produced by Actinoplanes liguriae NCIMB41362. J. Antibiot. 63, 351–358 (2010).
Crowther, G. S. et al. Evaluation of NVB302 versus vancomycin activity in an in vitro human gut model of Clostridium difficile infection. J. Antimicrob. Chemother. 68, 168–176 (2013).
Islam, M. R., Nagao, J., Zendo, T. & Sonomoto, K. Antimicrobial mechanism of lantibiotics. Biochem. Soc. Trans. 40, 1528–1533 (2012).
Shionogi and GlaxoSmithKline to collaborate on the research, development and commercialization of novel antibiotics targeting drug-resistant Gram-negative bacteria (Press release 28 October 2010) http://www.shionogi.co.jp/en/company/news/2010/pmrltj00000012ld-att/e_101028.pdf, (accessed on 31 May 2013).
Shionogi development pipeline May 2013 http://www.shionogi.co.jp/en/company/index.html, (accessed on 31 May 2013).
GlaxoSmithKline Product development pipeline 2013 February 2013 http://www.gsk.com/content/dam/gsk/globals/documents/pdf/GSK%202013%20Pipeline.pdf, (accessed 31 May 2013).
Kokryakov, V. N. et al. Protegrins: leukocyte antimicrobial peptides that combine features of corticostatic defensins and tachyplesins. FEBS Lett. 327, 231–236 (1993).
Lou, K.-J. A New Spin on Protegrin SciBX 3 doi:10.1038/scibx.2010.265 (2010).
Polyphor reports successful Phase I results for its Pseudomonas selective antibiotic POL7080 (Press release 4 March 2013) http://www.polyphor.com/assets/files/Press_Release/POL7080_Press%20Release_.pdf, (accessed on 31 May 2013).
Srinivas, N. et al. Peptidomimetic Antibiotics Target Outer-Membrane Biogenesis in Pseudomonas aeruginosa. Science 327, 1010–1013 (2010).
Jeong, J.-W. et al. In Vitro and In Vivo Activities of LCB01-0371, a New Oxazolidinone. Antimicrob. Agents Chemother. 54, 5359–5362 (2010).
Liu, C. & Fu, C. (MicuRx Pharmaceuticals, Inc.). Pharmaceutical composition used for treating bacteria infection CN 102485225 (2012).
Micurx Pharmaceuticals completes Phase 1 trial for MRX-I, a next-generation antibiotic (Press release 23 April 2012) http://www.micurx.com/news.htm, (accessed on 31 May 2013).
Vickers, R. et al(Summit Corporation PLC). Compounds for the treatment of Clostridium difficile associated disease WO2011/151621 (2011).
Positive Phase 1 Clinical Trial Results on SMT 19969 Reported (Press release 24 April 2013) http://www.summitplc.com/media/press-releases/, (accessed on 31 May 2013).
Trend, R. & Kasar, R. A. (Achaogen, Inc.). Preparation of N-((S)-3-amino-1-(hydroxyamino)-3-methyl-1-oxobutan-2-yl)-4-(((1R,2R)-2-(hydroxymethyl)cyclopropyl)buta-1,3-diynyl)benzamide useful in the treatment of bacterial infection. WO 2013/039947 (2013).
Raetz, C. R. H., Reynolds, C. M., Trent, M. S. & Bishop, R. E. Lipid a modification systems in Gram-negative bacteria. Annu. Rev. Biochem. 76, 295–329 (2007).
Zhang, J., Zhang, L., Li, X. & Xu, W. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) inhibitors: a new class of antibacterial agents. Curr. Med. Chem. 19, 2038–2050 (2012).
Achaogen Website Pipeline Section, http://www.achaogen.com/pipeline/lpxc, (accessed on 11 June 2013).
Kalidex Introduces Novel Fluoroquinolone, KPI-10, at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) (Press release 7 September 2012) http://www.prnewswire.com/news-releases/kalidex-introduces-novel-fluoroquinolone-kpi-10-at-the-52nd-interscience-conference-on-antimicrobial-agents-and-chemotherapy-icaac-168871396.html, (accessed on 11 June 2013).
Flamm, R. K., Biedenbach, D. J., Sader, H. S., Konrardy, M. L. & Jones, R. N. KPI-10 In Vitro Activity Tested Against Pathogens Commonly Associated with Community-Acquired Bacterial Pneumonia Infections. 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Poster F-2051 San Francisco, CA, USA.
Daiichi-Sankyo Major Pipeline as of 13 May 2013 http://www.daiichisankyo.com/rd/pipeline/pdf/Pipeline_EN.pdf, (accessed on 11 June 2013).
Higuchi, S., Onodera, Y., Chiba, M., Hoshino, K. & Gotoh, N. Potent in vitro antibacterial activity of DS-8587, a novel broad-spectrum quinolone, against Acinetobacter baumannii. Antimicrob. Agents Chemother. 57, 1978–1981 (2013).
Kyorin Pharmaceutical Main R&D Activities (4 February 2013) http://www.kyorin-pharm.co.jp/en/business/pdf/main_rd_activities_20130204_en.pdf, (accessed on 11 June 2013).
Crandon, J. L. & Nicolau, D. P. Human simulated studies of aztreonam and aztreonam-avibactam to evaluate activity against challenging Gram-negative organisms, including metallo-β-lactamase producers. Antimicrob. Agents Chemother. 57, 3299–3306 (2013).
Livermore, D. M. & Mushtaq, S. Activity of biapenem (RPX2003) combined with the boronate β-lactamase inhibitor RPX7009 against carbapenem-resistant Enterobacteriaceae. J. Antimicrob. Chemother. 68, 1825–1831 (2013).
Rempex Pharmaceuticals to Present Data at ICAAC on Carbavance™, a New Agent Designed to Treat Multi-Drug Resistant (MDR) Gram-Negative Bacteria (Press release 7 September 2012) http://www.rempexpharma.com/news/9-7-12, (accessed on 11 June 2013).
Butler, M. S. & Buss, A. D. Natural products - the future scaffolds for novel antibiotics? Biochem. Pharmacol. 71, 919–929 (2006).
Grushkin, D. Natural products emergent. Nat. Med. 19, 390–392 (2013).
Kirst, H. A. Developing new antibacterials through natural product research. Expert Opin. Drug Discov. 8, 479–493 (2013).
U.S. Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for Industry: Antibacterial Therapies for Patients With Unmet Medical Need for the Treatment of Serious Bacterial Diseases (July 2013) http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM359184.pdf, (accessed on 15 July 2013).
Zumla, A., Nahid, P. & Cole, S. T. Advances in the development of new tuberculosis drugs and treatment regimens. Nat. Rev. Drug Discov. 12, 388–404 (2013).
Butler, M. S. & Cooper, M. A. Screening strategies to identify new antibiotics. Curr. Drug Targets 13, 373–387 (2012).
This paper was prepared with the support of NHMRC grant AF511105. MSB and MAB are supported by a Wellcome Trust Seeding Drug Discovery Award (094977/Z/10/Z).
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Butler, M., Blaskovich, M. & Cooper, M. Antibiotics in the clinical pipeline in 2013. J Antibiot 66, 571–591 (2013). https://doi.org/10.1038/ja.2013.86
- antimicrobial resistance
- clinical trials
- drug development
- drug discovery
- natural product
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