Antibiotics in the clinical pipeline as of December 2022

The need for new antibacterial drugs to treat the increasing global prevalence of drug-resistant bacterial infections has clearly attracted global attention, with a range of existing and upcoming funding, policy, and legislative initiatives designed to revive antibacterial R&D. It is essential to assess whether these programs are having any real-world impact and this review continues our systematic analyses that began in 2011. Direct-acting antibacterials (47), non-traditional small molecule antibacterials (5), and β-lactam/β-lactamase inhibitor combinations (10) under clinical development as of December 2022 are described, as are the three antibacterial drugs launched since 2020. Encouragingly, the increased number of early-stage clinical candidates observed in the 2019 review increased in 2022, although the number of first-time drug approvals from 2020 to 2022 was disappointingly low. It will be critical to monitor how many Phase-I and -II candidates move into Phase-III and beyond in the next few years. There was also an enhanced presence of novel antibacterial pharmacophores in early-stage trials, and at least 18 of the 26 phase-I candidates were targeted to treat Gram-negative bacteria infections. Despite the promising early-stage antibacterial pipeline, it is essential to maintain funding for antibacterial R&D and to ensure that plans to address late-stage pipeline issues succeed.


Introduction
Antibiotics are the foundation of modern medicine but are becoming increasingly ineffective due to growing levels of antimicrobial resistance, threatening global health.The adverse impact of drug-resistant infections is highlighted by a seminal analysis of the global burden of bacterial antimicrobial resistance in 2019, with 1.27 million deaths directly attributed to, and 4.9 million deaths associated with, resistant bacteria [1].The development of new antibiotics, particularly new chemotypes or classes that can overcome existing resistance mechanisms, has been hindered by a failure of the healthcare system marketplace to adequately recognize and compensate for these products [2][3][4].In addition to improved generic antibiotic sales, branded antibiotic prices have fallen since 2001 [5], aggravating the economic challenges.Recognition of the antibiotic crisis has led to the establishment of targeted funding initiatives for antibiotic development such as the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) [6], INCATE [7], REPAIR Impact Fund [8], and the AMR Action Fund [9,10], testing of new incentives to reimburse pharmaceutical companies such as a subscription 'Netflix' model [11][12][13][14], and legislative initiatives such as the PASTEUR (The Pioneering Antimicrobial Subscriptions To End Up surging Resistance) Act in the United States [15,16].There has also been an increase in the number of "non-traditional" antibacterials [17][18][19][20][21] being actively evaluated in clinical trials [21,22].Non-traditional antibacterials can be small molecules, monoclonal antibodies (mAbs), proteins or live biotherapeutics such as bacteria and bacteriophages that primarily affect bacteria growth or virulence indirectly with varying mechanisms such as toxin binding, cell adherence reduction, inhibition of antivirulence targets and drug resistance modification [21].
To assess whether these activities are improving the status quo, we have monitored antibacterial drug development since 2011 with reviews published in 2019 [23], 2015 [24], 2013 [25] and 2011 [26].Complementary reviews with different approaches and analyses (but often with few or no chemical structures) are available.The Pew Trusts developed an online pipeline tracker that allows the visualization of changes in the pipeline from 2014-2020 [27], but their antibiotic resistance project was discontinued in December 2021 [28].In 2022, the WHO published a report on antibacterial agents in both preclinical and clinical development in 2021 [22] and a journal article in 2022 [21].The WHO also recently reviewed the preclinical and clinical antibacterial vaccine pipeline [29].A 2021 review critically analyzed why compounds with Gram-negative (Gve) activity have fallen out of the pipeline over the past decade [30], while two 2020 reviews covered both the clinical [31] and preclinical [32] antibacterial pipelines, with a third providing an overview of 'novel' antibacterial agents in various stages of development [33].Reviews of patents from 2010-2021 focusing on compounds with activity against multi-drug resistant (MDR) G-ve bacteria [34], antibacterial combinations [35], and discovery strategies [36] have also been published.
This review catalogs the small molecule antibacterial drugs launched since January 2012 in Table 1 and the yearly number of first-time antibacterial drugs launched by year since 2000 (Fig. 1, Table S1).International Nonproprietary Names (INN) are used for compound names when available.For completeness, Table 2 lists the nontraditional antibacterial drugs launched during this period.The new antibacterial drugs approved since the previous 2019 review [23], levonadifloxacin (1) and its prodrug alalevonadifloxacin (2), and contezolid (4) (Fig. 2), are analyzed.Consistent with previous reviews in this series [23][24][25][26], small molecule antibacterials (both traditional and non-traditional) and β-lactamase/β-lactam inhibitor (BL/ BLI) combinations that are being evaluated in phase-I, -II, or -III clinical trials and under pre-approval regulatory evaluation as of 31 December 2022 are summarized (Tables 3-6, Figs.[3][4][5][6][7][8][9][10][11][12][13], along with their development status, mode of action (MoA), spectra of activity, historical discovery, and lead compound origin (natural product (NP), synthetic (S) or protein/mammalian peptides (P)).In the previous 2019 review [23], one antibody drug conjugate (ADC), DSTA4637S, was discussed, but its development has since been halted (Table 7).The clinical trial study codes, which are predominantly from ClinicalTrials.gov(NCT), are listed in parentheses for each trial, while nonregistered trials are referenced at least in a Press Release or peer-reviewed publication.An overview of the drug development and approval process, on-line clinical trial databases antibiotic clinical trial categories and abbreviations can be found in the Supplementary Information.Prodrugs are grouped together with their active metabolites, while ongoing trials of antibacterial drugs already approved anywhere in the world are presented in Table S2.
Compounds where no development activity has been identified since 2018 are listed in Table 7.The antibacterials in clinical development have been further analyzed by phase and source derivation (Fig. 14) and also compared with data reported in our 2011 [26], 2013 [25], 2015 [24] and 2019 [23] reviews (Fig. 15).An analysis of new antibacterial pharmacophores (Table 8, Figs.16 and 17) and administration routes (Figs.S1 and S2) is also included.The administration routes in this review are as follows: po (oral), IV/po (intravenous oral switch); IV (intravenous), IV/topical (IV and topical), po topical (orally administered for Clostridioides difficile (formally Clostridium [37]) infections (CDI)), oral, topical and inhalation.The 'po topical' term distinguishes between oral administration to treat C. difficile infections and the gut microbiome compared to topical administration via creams, sprays, and eyedrops.
Data in this review were obtained by analyzing the scientific literature and internet sources such as company and funding organization websites, clinical trial registers, The Pew Charitable Trusts (Philadelphia, PA, USA) [28] and World Health Organization (WHO) (Geneva, Switzerland) pipeline analyses [21,22] and biotechnology newsletters.Every effort has been made to ensure the accuracy of this data; however, it is possible that compounds in the early stages of clinical development have been overlooked as there is limited information available in the public domain.

Antibacterial drugs launched from January 2013 to December 2022
In the last 10 years, 19 new small molecule antibacterial drugs (eight NP-derived and 11 synthetic-derived) and four new BL/BLI combinations have been approved (Table 1 and S1, Figs. 1 and 2).Among these 19 antibacterial drugs, none was first-in-class, with the last being bedaquiline in 2012 (diarylquinoline class), which also was the first new tuberculosis (TB) drug class since 1963 [38].Although the semi-synthetic pleuromutilin derivative lefamulin was approved in 2019 for systemic use for community-acquired bacterial pneumonia (CABP) infection, a topically administered pleuromutilin, retapamulin, was approved in 2007.While new classes of G-ve antibacterial drugs have been approved, new exemplars within existing classes, especially BL/BLI combinations, also show improved activity profiles against resistant G-ve bacteria.
Levonadifloxacin (1) (Emrok, WCK-771; IV), which is the arginine salt of the fluoroquinolone S-(-)-nadifloxacin, and its alanine prodrug alalevonadifloxacin (2) (Emrok O, WCK-2349; po) [39][40][41] were developed by Wockhardt (Mumbai, Republic of India).Both the IV and oral formulations were approved in January 2020 by the Indian Central Drugs Standard Control Organization (CDSCO) for the treatment of acute bacterial skin and skin structure Antibiotics in the clinical pipeline as of December 2022 infections (ABSSSI), including diabetic foot infections and concurrent bacteremia [42,43].Levonadifloxacin (1) has activity against G+ve bacteria including MRSA, as well as some G-ve bacteria [41], and a prescription-event monitoring study was recently published [44].Racemic nadifloxacin was first approved in 1993 to topically treat acne and MRSA infections [45].
Three non-traditional antibacterial drugs (two mAbs and one biotherapeutic) were launched between 2013 and 2022 to treat bacterial infections (Table 2), compared to 19 traditional antibacterial drugs launched during this period (     Obiltoxaximab [51,52] is a mAb that neutralizes harmful toxins produced by Bacillus anthracis that was approved using the US FDA Animal Rule based on their efficacy in relevant animal models and safety in phase-I studies.Another mAb that also neutralizes B. anthracis toxins, raxibacumab [52,53], was similarly approved in 2012.The mAb bezlotoxumab, which binds to toxin B produced by C. difficile [54,55], was approved in 2016 to help prevent the recurrence of CDI after successfully completing two phase-III trials [56,57]. In November 2022, a live biotherapeutic product, RBX2660 (Rebyota), was approved by the US FDA [58] to help prevent CDI following antibiotic treatment, based on phase-III trial data [59].RBX2660 is a liquid suspension donor fecal microbiota that has been screened for bacterial, viral and parasitic pathogens [60,61] that was developed by Rebiotix Inc (Roseville, MN, USA), which is part of Ferring Pharmaceuticals (Saint-Prex, Switzerland).There is also another phase-III trial (NCT03931941) in progress.
Although outside the cut-off period, another non-traditional antibacterial product, Vowst (SER-109), developed by Seres Therapeutics Inc (Cambridge, MA, USA) and Nestlé Health Science (Hoboken, NJ, USA) was approved by the US FDA on 26 April 2023. 1

Compounds undergoing clinical evaluation
Direct acting small molecules, mammalian-derived peptides and polymeric compounds currently undergoing clinical trials or under regulatory evaluation for the treatment of bacterial infections on 31 December 2022 are detailed in the following tables and figures: NDA and phase-III in Table 3 and 6 with structures in Figs. 3, 4, 11, and 12, phase-II in Table 4 with structures in Figs.5-7, and phase-I in Tables 5 and 6 with structures in Figs.8-10 and 13.Non-traditional antibacterial candidates that are not small molecules such as biotherapeutic microbiome modulation, phage therapy, and antibodies have not been included in this review.
Compounds in NDA/MAA filing (Table 3, Fig. 3) [62] that is being developed by FUJIFILM Toyama Chemical Co., Ltd.(Tokyo, Japan).In April 2019, an NDA was submitted to the Japanese Pharmaceuticals and Medical Devices Agency (PDMA) for use of 5 as a treatment for otorhinolaryngological bacterial infections.Although there have been no subsequent updates, 5 is still listed on their November 2022 pipeline as 'NDA filing' for otorhinolaryngology and as phase-III for respiratory infectious disease [63].Solithromycin (5) was previously being developed in the USA and Europe for CABP but development was halted in 2016 and 2017 respectively [64].Compounds in phase-III trials (Table 3, Fig. 4) Sulopenem (6) (CP-70,429), which is a synthetic thiopenem BL first developed by Pfizer (New York, NY, USA) in the 1990s [65][66][67][68], and its prodrug sulopenem etzadroxil (7) (PF-03709270; po) are being developed as treatments for G-ve infections by Iterum Therapeutics (Dublin, Ireland).
To date, three phase-III trials have been completed and have reported results: complicated intra-abdominal infections (cIAI) (NCT03358576), cUTI (NCT03357614) [69] and uUTI (NCT03354598) [70].In November 2020, Interim filed an NDA for uUTIs with the FDA [71] for orally administered sulopenem etzadroxil (7) in combination with probenecid (8) [72].Probenecid ( 8) is a marketed drug for gout and hyperuricemia that increases uric acid production, which inhibits BL tubular renal secretion that leads to a longer antibiotic half-life and higher serum concentrations [73].However, the FDA issued a Complete Response Letter Fig. 4 Structures of compounds in phase-III clinical trials (Table 3) Fig. 3 Structure of the antibacterial in the NDA and MAA development stage (Table 3) (CRL) in July 2021 that indicated that the NDA was not approvable in its present form [74].In response to this CRL, Iterum initiated another phase-III trial (NCT05584657) in October 2022 to investigate sulopenem etzadroxil (7) + probenecid (8) compared to amoxicillin + clavulanic acid for uUTI, which is scheduled to finish in March 2024.Nafithromycin (9) (WCK 4873; po) is an orally bioavailable ketolide being developed by Wockhardt Limited (Mumbai, Republic of India) that is being evaluated in a phase-III trial (CTRI/2019/11/021964) in India as an oral treatment for CABP.Nafithromycin (9) has broad spectrum antibacterial activity against G+ves such as S. pneumoniae and S. aureus and G-ves such as Haemophilus influenzae, Moraxella catarrhalis, Legionella pneumophila, Mycoplasma pneumoniae and Chlamydophila pneumoniae [75][76][77][78].
Benapenem (12) (IV) is a carbapenem that completed a phase-II/III trial in May 2020 (NCT04505683) as an intravenous treatment for cUTI, including pyelonephritis, by Sihuan Pharmaceutical (Beijing, People's Republic of China).Benapenem (12) is structurally related to ertapenem and has a similar extended human half-life of 7 h, which supports once-daily IV dosing like ertapenem, an advantage over other carbapenems that require multiple daily dosing due to shorter half-lives [94,95].
Epetraborole (13) (GSK2251052, AN3365, and BRII-658; po) is a benzoxaborole leucyl-tRNA synthetase (LeuRS) inhibitor [96], which is a new antibacterial target, being evaluated by AN2 Therapeutics (Menlo Park, CA, USA) in a phase-II/III (NCT05327803) against treatment-refractory Mycobacterium avium complex (MAC) lung disease.MAC accounts for up to 85% of non-tuberculosis mycobacteria (NTM) related lung disease [97].Epetraborole (13) has also been reported to have in vivo activity against Mycobacterium abscessus, another NTM involved in lung infections [98,99].Epetraborole (13) was originally developed as a treatment for G-ve infections in phase-II trials for cUTI (NCT01381549) and cIAI (NCT01381562) but these studies were halted due to resistance developing in patients during the cUTI trial [100].Brii Biosciences (Durham, NC, USA and Shanghai, People's Republic of China) have licensed 13 for development in the Greater China region [101].
Traditional antibacterial compounds in phase-II trials (Table 4, Figs. 5 and 6) Sanfetrinem cilexetil (14) (GV-104326; po) is a 1-(cyclohexyloxycarbonyloxy)ethyl ester prodrug of the trinem (tricyclic carbapenem) sanfetrinem (15) first developed in the 1990s by Glaxo Wellcome, which is now part of GSK (London, UK).Sanfetrinem (15) is active against a range of G+ve (e.g., S. aureus, S. pneumoniae and H. influenzae) and G-ve bacteria (e.g., E. coli, M. catarrhalis) [102][103][104].Although sanfetrinem cilexetil (14) successfully completed a phase-II trial for respiratory infections in 1999, no further development work was undertaken until GSK started a phase-II trial (NCT05388448) in May 2022, which is evaluating 14 against rifampicin-susceptible pulmonary TB [105].There has been a recent surge in interest in investigating carbapenem-type antibacterials as TB treatments, as evidenced by TASK (Cape Town, South Africa) leading a study that showed meropenem (66) in combination with amoxicillin + clavulanic acid had efficacy in a phase-II TB trial (NCT02349841) [106], as well as a consortium of private and public organizations that screened approximately 8,900 carbapenems against Mycobacterium tuberculosis (Mtb) [107].
MGB-BP-3 (16) (po topical) is a DNA binding antibacterial being developed by MGB Biopharma (Glasgow, UK) that successfully completed a phase-II trial (NCT03824795) in May 2020 for the treatment of C. difficile-associated diarrhea (CDAD) [108].MGB-BP-3 (16) was discovered at the University of Strathclyde (Glasgow, UK) and was inspired by the actinomycetes-derived minor groove binders, distamycin, netropsin and thiazotropsin   [109,110].In addition to activity against C. difficile, 16 has activity against a range of G+ve bacteria including S. aureus and Enterococcus faecalis but is not active against G-ve bacteria due to a lack of intracellular accumulation [111].It was shown that two molecules of 16 bound to the minor groove of dsDNA, which then interfered with transcription, the supercoiling action of gyrase, and the relaxation and decatenation by topoisomerase IV enzymes in vitro [111].This is mechanistically distinct from fluoroquinolones that cause an increase in double strand breaks, as well as induce recA and lexA SOS responses.A preprint has reported that 16 also binds to and inhibits multiple essential promoters on the S. aureus chromosome [112].Furthermore, 16 is equally effective against ciprofloxacinresistant and ciprofloxacin-susceptible strains [113].
Exeporfinium chloride (17) (XF-73; topical) is a photosensitizing porphyrin derivative with broad-spectrum G+ve activity [114][115][116] and a low propensity for developing resistance [117] being developed by Destiny Pharma (Brighton, UK).Exeporfinium chloride (17) successfully completed a phase-II trial (NCT03915470) in March 2021 that investigated its activity against nasal S. aureus in patients at risk of post-operative infections.Destiny Pharma plans to start two phase-III nasal decolonization trials in 2024 after securing a partnering deal [118].
Synthetic cannabidiol (18) (CBD, BTX 1801; topical) has been evaluated in a phase-II trial (ACTRN12620000456954) by Botanix Pharmaceuticals (Perth, Australia) for the clearance of nasally colonized S. aureus, as well as in phase-II trials in acne (BTX 1503, NCT03573518) and atopic dermatitis (BTX 1204, NCT03824405).Cannabidiol (18) is the major non-psychoactive component of cannabis (Cannabis sativa and C. indica) and its G+ve antibacterial activity, along with that of the major psychoactive compound Δ 9tetrahydrocannabinol, was reported as having potential as a topical antibacterial in 1976 [119].Anti-MRSA activity of 18 was later confirmed in 2008 [120] and 2020 [121] studies, along with other analogs.In 2021, an in-depth study showed that 18 was active against drug resistant strains of S. aureus, S. pneumoniae, E. faecalis, Cutibacterium acnes and C. difficile, less active against S. pyogenes and S. agalactiae, weakly active against Mycobacterium smegmatis and barely active against Mtb [122].While cannabidiol (18) was inactive against E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii, it also displayed activity against four G-ve bacteria: N. gonorrhoeae, Neisseria meningitidis, M. catarrhalis and L. pneumophila [122].It was also demonstrated that 18 was active against MSSA and MRSA biofilms, was active in topical in vivo models (though highly formulation-dependent) and that its MoA involved cytoplasmic membrane disruption [122].It was recently shown that 18 could also act as an adjuvant with bacitracin, a cell wall inhibitor, via inhibition of  Recce-327 is a polymer and its structural units have not been disclosed Antibiotics in the clinical pipeline as of December 2022 undecaprenyl pyrophosphate dephosphorylation [123].Genomic analysis demonstrated that less susceptible S. aureus strains contained mutations in the transporter farE/farR efflux pump system [123].Additionally, screening of the Nebraska Transposon Mutant Library identified that strains with insertions involved in menaquinone biosynthesis had increased susceptibility to 18 that could be reversed by the addition of menaquinone [123].The menaquinone biosynthesis pathway has been shown to be a promising drug target for S. aureus [124,125].TNP-2092 (19) (CBR 2092; IV) is being developed by TenNor Therapeutics (Suzhou, People's Republic of China) and completed a phase-II trial (NCT03964493) for the treatment of G+ve ABSSSI infections using IV dosing in September 2020.TenNor have also evaluated capsule administration of 19 for hyperammonemia/hepatic  4) encephalopathy in a phase-II trial with patients with liver cirrhosis [126,127], while a phase-I trial (NCT04294862) for Prosthetic Joint Infection (PJI) employed IV administration [128].TNP-2092 ( 19) is a rifamycinquinolizinone (lead ABT-719) hybrid G+ve antibacterial discovered by Cumbre Pharmaceuticals [126,129,130] and  4) its MoA is via inhibition of the targets of both antibacterial components: RNA polymerase (rifamycin) and DNA gyrase and topoisomerase IV (quinolone/quinolizinone) [131].
TNP-2198 (20) (IV) is another hybrid being developed by TenNor Therapeutics (Suzhou, People's Republic of China); in this case, a rifamycin-metronidazole hybrid [132] for microaerophilic and anaerobic infections, which include gastrointestinal diseases associated with Helicobacter pylori, bacterial vaginosis and CDAD [133].An H. pylori phase-II trial (CTR20220625 [134]) of capsules of 20 in combination with rabeprazole tablets (used to treat peptic ulcer disease) and amoxicillin capsules was completed in September 2022.An X-ray crystal structure was recently published that showed 20 bound to the rifamycin binding site on RNA polymerase with the nitroimidazole portion interacting directly with the DNA template-strand in the RNA polymerase active-center cleft, forming a hydrogen bond with a base of the DNA template strand [132].This is supportive of RNA polymerase inhibition being involved in the MoA of 20.
Peceleganan (23) (PL-5, V 681 ; topical) is a 26-mer αhelical cationic hybrid peptide of cecropin A and melittin B [144,145] being developed by Jiangsu ProteLight Pharmaceutical and Biotechnology (Jiangyin, People's Republic of China).Peceleganan ( 23) is administered by spray and has successfully completed a phase-II trial in China (ChiCTR2000033334) for the treatment of bacterial wound infections [146].No levels of 23 were detected in the patients' blood.This indicated that there was minimal or no systemic exposure [146], a significant consideration since some cationic peptides have a history of causing nephrotoxicity.Peceleganan (23) has activity against both G+ve and G-ve bacteria [144,145] and there are plans to start a phase-III trial in 2023.
Recce-327 (R327; topical and IV) is an acrolein polymer with a molecular weight range of 1-1.5 kDa [147] being evaluated by Recce Pharmaceuticals (Perth, Australia) in a phase-I/II (ACTRN12621000412831) for the treatment of G+ve and G-ve burn wound infections.A phase-I trial (ACTRN12621001313820) using IV administration of Reece-327 is being conducted with the goal of developing the polymer for serious bacterial infections such as sepsis in the future.It has been reported that the polymer disrupts bacterial cellular bioenergetics via membrane potential and/ or ATP synthesis [148].
Pravibismane (24) (MBN-101, bismuth ethanedithiol, BisEDT; topical) is a broad spectrum antibacterial with antibiofilm activity [149] that is being developed by Microbion Corporation (Bozeman, MT, USA).A phase-II trial (NCT05174806) evaluating 24 as a topical treatment for diabetic foot infections started in June 2022, while a phase-II trial (NCT02436876) using intraoperative administration in patients diagnosed with an orthopedic infection was completed in July 2018.This clinical work is supported by the Cystic Fibrosis Foundation (Bethesda, MD, USA) and CARB-X (Boston, MA, USA).It has been reported that 24 can cause bacterial membrane depolarization, which disrupts cellular bioenergetics [150].Bismuth has intrinsic antibacterial activity and is a component of Pepto Bismol ® (bismuth subsalicylate) [151] and Xeroform ® (bismuth tribromophenate) [152], and is used in combination with antibiotics and a proton pump inhibitor to treat H. pylori infections [153].There has recently been a resurgence in interest in the antibacterial activity of metal complexes [154,155].
DNV-3837 (25) (MCB-3837; IV) is a phosphate prodrug of the oxazolidinone-quinolone hybrid DNV-3681 (26) (MCB-3681) being developed by Deinove (Montpellier, France).It is currently being evaluated in a phase-II CDI trial (NCT03988855) with IV administration [156].Unfortunately, Deinove entered receivership proceedings in November 2022 [157].The IV administration contrasts with most other antibacterials being developed for CDI, including non-traditionals [17,21], that are almost exclusively delivered orally with little or no systemic distribution (po topical).DNV-3837 (25) also showed G+ve activity against MRSA, Francisella tularensis and B. anthracis [158][159][160].5) Ibezapolstat ( 27) (ACX-362E; po topical) is a bissubstituted guanine derivative that is a bacterial DNA polymerase IIIC inhibitor [161][162][163][164] that is being evaluated in a phase-II CDI trial (NCT04247542) [165] by Acurx Pharmaceuticals (White Plains, NY, USA).DNA polymerase IIIC is a new target for clinical development and is an essential enzyme in bacteria with low guanine and cytosine content, such as Bacillus, Clostridioides, Enterococcus, Mycoplasma, Lactobacillus, Listeria, Pneumococcus, Staphylococcus and Streptococcus [163].CRS3123 (28) (REP3123; po topical) is a methionyl tRNA synthetase (MetRS) inhibitor (new diaryldiamine class) being developed by Crestone (Boulder, CO, USA) that selectively acts on S. aureus and C. difficile MetRS with little effect on G-ve and mammalian orthologs [166,167].CRS3123 (28) prevents C. difficile sporulation, which leads to the inhibition of toxin production, and spares most normal gut flora [168].CRS3123 (28) has completed two phase-I trials (NCT02106338 and NCT01551004) [169,170] and is currently being evaluated in a CDI phase-II trial (NCT04781387) versus a vancomycin comparator.In the previous pipeline review [23], 28 was listed as having its development halted or discontinued.This a reminder that relatively long delays can occur in antibacterial drug development, which have been exacerbated by the COVID-19 pandemic due to disruptions to clinical trial enrollments and day-to-day operations of many organizations [171].
BTZ-043 (34) (po) is the first member of a new benzothiazinone (BTZ) class of TB antibacterials that completed a phase-I/II trial (NCT04044001) in May 2022.This study evaluated the safety, tolerability and EBA of 34, and was led by the EDCTP (The Hague, Netherlands).BTZ-043 (34) inhibits the essential mycobacterial cell wall biosynthesis enzyme decaprenylphosphoryl-β-D-ribose (DPR) 2′-oxidase (DprE1) via in vivo reduction of the nitro group, generating a reactive nitroso intermediate that forms a covalent semi-mercaptal adduct with cysteine-387 [202][203][204][205][206]. It has been shown that BTZs can be dearomatized in vivo through the formation of a Meisenheimer complex, which could also reduce their in vivo halflives [207,208].A BTZ analog, macozinone (53, Fig. 9) is being evaluated in a phase-I trial.
TBA-7371 (37) (po) is a substituted 1,4-azaindole that is being developed as a new TB treatment by the Global Alliance for TB Drug Development (New York, NY, USA), the Foundation for Neglected Disease Research (Bangalore, Republic of India) and the Bill & Melinda Gates Medical Research Institute (Cambridge, MA, USA).TBA-7371 ( 37) is currently being evaluated in a phase-II EBA and pharmacokinetic (PK) trial (NCT04176250) in patients with rifampicin-sensitive TB.TBA-7371 ( 37) is a non-covalent DprE1 inhibitor discovered by scaffold hopping from telacebec (31), which has a different mechanism [213][214][215].
Sudapyridine (38) (WX-081; po) is a bedaquiline analog with a chlorophenyl-methoxypyridyl group replacing the bedaquiline bromo-2-methoxy-3-quinolyl substituent [216] being developed by Shanghai Jiatan Biotech (Shanghai, People's Republic of China).Sudapyridine (38) is being evaluated in a phase-II EBA trial (NCT04608955) in patients with susceptible and drug-resistant TB.Sudapyridine (38) has a similar in vitro and in vivo activity profile to bedaquiline, but had no adverse effects on blood pressure, heart rate, or qualitative ECG parameters during nonclinical toxicology studies [217].Sudapyridine (38) also has in vitro activity against most NTM species [218].
Pyrifazimine (39) (TBI-166; po) is a clofazimine analog [219] (riminophenazine class) that completed a phase-II EBA TB trial (NCT04670120) in June 2021 run by the Institute of Materia Medica (Shanghai, People's Republic of China), Chinese Academy of Medical Sciences (Beijing, People's Republic of China) and Peking Union Medical College (Beijing, People's Republic of China).Although clofazimine has been used to treat leprosy (Mycobacterium leprae infections) since 1962 and was recently incorporated into some short-course MDR-TB regimens [220,221], its tissue accumulation can cause skin discoloration that can take months to clear.Pyrifazimine (39) was designed to maintain activity against TB, have improved PK/pharmacodynamics (PD) properties, and cause less skin discoloration [222][223][224][225].
Dovramilast (42) (CC-11050, AMG-634; po) is an isoindole phosphodiesterase type 4 (PDE4) inhibitor being developed for TB [231,232] and leprosy type 2 reactions by Medicines Development for Global Health (Melbourne, Australia), which licensed 42 from Amgen (Thousand Oaks, CA, USA) in December 2020 [233,234].Dovramilast ( 42) is being evaluated in a phase-II trial (NCT03807362) at The Leprosy Mission Nepal (Katmandu, Nepal) for patients with erythema nodosum leprosum (ENL), which is an inflammatory disorder triggered by leprosy.Another phase-II trial (NCT02968927) run by The Aurum Institute NPC (Johannesburg, South Africa) has been completed [235,236].PDE4 inhibitors are an adjunctive hostdirected therapy designed to modulate the inflammatory response to Mtb infection by reducing, but not fully blocking, TNF-α production by the host cells.The NCT02968927 trial used 42 in combination with 2HRZE/ 4HR therapy, which is 2 months of isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E), followed by a continuation phase of 4 months of isoniazid and rifampicin, while the NCT03807362 trial examines the safety and efficacy of CC-11050 as a monotherapy.
Traditional antibacterial compounds in phase-I trials (Table 5, Figs. 8 and 9) SPR206 (43) (IV) is a polymyxin analog being developed by Spero Therapeutics (Cambridge, MA, USA) with activity against MDR G-ve bacteria [237] and reduced nephrotoxicity compared to polymyxin.SPR206 (43) has completed three phase-I trials (NCT03792308, NCT04868292, and NCT04865393), with a phase-II trial planned for Q4 2023 [238].Everest Medicines (Shanghai, People's Republic of China) had licensed the rights for 43 in China, South Korea and several Southeast Asian countries [239], while Pfizer (New York, NY, USA) has the remaining rights outside of the USA [238].
MRX-8 (IV) is another polymyxin analog being developed by MicuRx (Hayward, CA, USA and Shanghai, People's Republic of China) against G-ve bacteria [240][241][242] that completed a phase-I trial in 2021 (NCT04649541), while another phase-I is ongoing in China [243].Although MRX-8's structure has not been publicly disclosed, it is a polymyxin B analog with a fatty acid tail linked via a polar ester group to form a 'soft' prodrug [241,244].
QPX-9003 (44) (F365, BRII-693; IV) is also a polymyxin derivative being developed by Qpex Biopharma (San Diego, CA, USA).It is a potential treatment for P. aeruginosa and A. baumannii infections and completed a phase-I trial in July 2022 (NCT04808414) [245].QPX-9003 (44) was reported by researchers at Monash University (Melbourne, Australia) and Qpex to have reduced nephrotoxicity, acute toxicity and in vitro lung surfactant inactivation compared to other polymyxins [246].Brii Biosciences (Durham, NC, USA and Shanghai, People's Republic of China) have licensed QPX-9003 (44) for development in the Greater China region [101].
RG6319 (administration route not disclosed) is an inhibitor of LepB, which is an E. coli Type I signal peptidase (SPase), listed on Roche's (Basel, Switzerland) pipeline as being evaluated in a phase-I clinical trial for cUTI [247].SPases are enzymes that hydrolyze N-terminal signal peptides from proteins that are secreted across the cytoplasmic membrane and have a critical role in the viability and virulence of bacteria [248].Although the structure of RG6319 has not been disclosed, Genetech (San Francisco, CA, USA) and The Scripps Research Institute (La Jolla, CA, USA) have been evaluating derivatives of the arylomycins, which are Streptomyces-derived SPase inhibitors, such as G0775 [249,250].
Apramycin (46) (EBL-1003; IV) is an aminoglycoside being developed by Juvabis AG (Zurich, Switzerland) that completed a phase-I trial (NCT04105205) in October 2020.A new phase-I trial (NCT05590728) was recently started by the National Institute of Allergy and Infectious Diseases (NIAID; Rockville, MD, USA).Apramycin (46) has activity against carbapenem-and aminoglycoside-resistant Enterobacteriaceae, A. baumannii and P. aeruginosa [255,256].Apramycin (46) has been widely used as a veterinary antibiotic to treat E. coli and other G-ve infections [257], with European approval to treat colibacillosis and salmonellosis in calves, bacterial enteritis in pigs, colibacillosis in lambs and E. coli septicemia in poultry [258].It was discovered in the 1960s at Eli Lilly & Co (Indianapolis, IN, USA) as a NP produced by Streptomyces tenebrarius [259,260].PLG0206 (47) (WLBU2; topical and IV) is a 24 residue membrane disrupting cationic peptide [261,262] being evaluated by Peptilogics (Pittsburgh, PA, USA) in a phase-I trial (NCT05137314) for its potential to treat PJI in conjunction with the DAIR (debridement, antibiotics, and implant retention) surgical procedure after total knee arthroplasty.PLG0206 (47) has also successfully completed a phase-I trial with IV administration [263].PLG0206 (47) has broad spectrum activity against G+ve and G-ve bacteria, including biofilms [261,264,265].
PL-18 (48) (HPRP-A1; topical) is a 15-mer α-helical cationic peptide derived from the N-terminus of the H. pylori ribosomal protein L1 (RpL1) that is being developed by Jiangsu ProteLight Pharmaceutical and Biotechnology (Jiangyin, People's Republic of China).In August 2022, 48 started a phase-I trial (NCT05340790) in Australia for bacterial vaginosis using suppository administration.PL-18 (48) has activity against G-ve and G+ve bacteria [144,145,266,267] and fungi [266], as well as induction of HeLa cell apoptosis [268] and hemolytic activity [266,267].These off-target activities suggest why topical administration is required for 48.
Murepavadin (49) (POL7080, RG7929; inhalation) is a synthetic 14-mer cyclic peptide derived from protegrin I being developed by Spexis (Basel, Switzerland), which was formed through a merger of EnBiotix and Polyphor in December 2021.Murepavadin ( 49) has potent and selective activity against P. aeruginosa via binding to the N-terminal of the β-barrel protein LptD (Imp/OstA), a novel MoA [269][270][271].Murepavadin ( 49) is reported to be in a phase-I trial for cystic fibrosis using inhaled administration [272], and was previously investigated in two phase-III trials for the treatment of Pseudomonas nosocomial pneumonia (NCT03582007) and VAP infections (NCT03409679).However, these trials were halted due to adverse eventsan increase in serum creatinine and acute kidney injury in the nosocomial pneumonia trial in 2019 [273].TXA709 (50) (po) is an anti-MRSA prodrug of TXA707 (51) that has been evaluated in a phase-I trial conducted by TAXIS Pharmaceuticals (Monmouth Junction, NJ, USA) [274].TXA707 ( 50) is an inhibitor of the new antibacterial target FtsZ, which is the bacterial homolog of tubulin that plays a critical role in bacterial cell wall division in both G +ve and G-ve bacteria [275,276].Prolysis Ltd (Oxford, UK) originally identified PC190723 [277][278][279] and replacement of its Cl substituent with a CF 3 group in TXA707 (51) enhanced metabolic stability, PK properties and in vivo efficacy against S. aureus [280,281].
RG6006 (RO7223280, Abx MCP; IV) is being developed by Roche (Basel, Switzerland) and a phase-I trial (NCT05614895) was started in December 2022 in critically ill participants with bacterial infections using IV administration.RG6006 will be developed as a treatment for A.
Anti-mycobacterial compounds in phase-I trials (Table 5, Fig. 9) Macozinone (53) (PBTZ169; po) is a benzothiazinone (BTZ) derivative [289] that was evaluated in a phase-II EBA TB trial (NCT03334734) by Nearmedic Plus LLC (Moscow, Russia), but the trial was discontinued in February 2018 due to slow enrollment.The Innovative Medicines for Tuberculosis (iM4TB) Foundation (Lausanne, Switzerland) is leading the development of 53 in the rest of the world and completed a Phase-I trial (NCT03776500) in March 2020.Macozinone ( 53) is a second generation analog of BTZ043 (34, Fig. 6) with the same MoA (inhibition of the mycobacterial cell wall biosynthesis enzyme DprE1) with superior physicochemical properties [289]; however, efforts have been undertaken to improve its PK and PD properties [290].
TBI-223 (54) (po) is an oxazolidinone [291] being developed by the TB Alliance (New York, NY, USA) and the Institute of Materia Medica (Shanghai, People's Republic of China) that has completed two phase-I trials (NCT03758612 and NCT04865536).TBI-223 (54) was recently found to be active against S. aureus in MRSA mouse models [292].
TBAJ-876 (55) (po) is a bedaquiline analog (diarylquinolines class) with activity against Mtb [293] and M. abscessus [294], and minimal hERG channel inhibition [295,296] that was discovered at the University of Auckland (Auckland, New Zealand).TBAJ-876 ( 55) is now being developed by the TB Alliance (New York, NY, USA) and completed a phase-I trial (NCT04493671) in November 2022, which focused on safety, tolerability, and PK.In September 2022, another phase-I trial (NCT05526911) was initiated that also evaluates its effects on CYP3A4 and P-glycoprotein.Like bedaquiline, 55 is an inhibitor of mycobacterial F-ATP synthase [297] but does not retain bedaquiline's protonophore activity [298].Cryogenic electron microscopy (cryo-EM) was recently used to show the binding of 55 to the F o domain in M. smegmatis F 1 F o -ATP synthase [299].
TBAJ-587 (56) (po) is another bedaquiline analog [295] with variations in the substituents on one pyridyl ring that lead to more potent in vitro and in vivo activity against Mtb [300].TBAJ-587 ( 56) is currently in a phase-1 trial (NCT04890535) to evaluate its safety, tolerability, and PK.GSK2556286 (57) (GSK-286; po) is a substituted uracil derivative being evaluated by GSK (London, UK) in a phase-I trial (NCT04472897) as a potential TB treatment [301].GSK2556286 (57) was discovered by screening against Mtb that resides within human (THP-1) macrophage-like differentiated monocytes and had an IC 50 of 0.07 µM [302].In addition, 57 required cholesterol to show activity in an axenic culture and resistance mutations were mapped to Mtb adenylyl cyclase (cya) Rv1625c [302][303][304], which has been implicated in cholesterol utilization [305].This is a new MoA.
Non-traditional antibacterial compounds in phase-I trials (Table 5, Fig. 10) BVL-GSK098 (58) [306] (po) is the first member of a new non-traditional, anti-TB antibacterial class (spiroisoxazoline) being developed by BioVersys (Basel, Switzerland) and GSK (London, UK).BVL-GSK098 ( 58) completed a phase-I trial (NCT04654143) in May 2022.BVL-GSK098 works through inactivation of a Mtb TetR-like repressor, EthR2, which reverses ethionamide (59)-acquired resistance and increased basal sensitivity to 59 [307,308].A phase-II EBA trial (NCT05473195) is scheduled to evaluate ethionamide (59) with or without BVL-GSK098 (58) in participants with rifampicin-and isoniazid-susceptible pulmonary TB.GSK3882347 (po) is an E coli Type 1 fimbrin D-mannose specific adhesin (FimH) inhibitor being evaluated by GSK (London, UK) and Fimbrion Therapeutics (St. Louis, MO, USA) with support from CARB-X (Boston, MA, USA) [309].GSK3882347 completed a phase-I trial (NCT04488770) in May 2021 and is currently being evaluated in a Phase-Ib trial (NCT05138822) in participants with acute uUTI.A majority of UTIs are caused by uropathogenic E. coli (UPEC) [310], which use their type 1 pili to adhere to the cell wall via FimH adhesin [311].Targeting the mannose-binding lectin domain of FimH prevents UPEC from binding to the bladder wall and is a promising antivirulence approach for UTI and Crohn's Disease [312][313][314].Although the structure of GSK3882347 has not been publicly disclosed, it is likely to be a mannosederived biphenyl derivative [315].
ALS4 (po) is an S. aureus anti-virulence antibacterial being developed by Aptorum Therapeutics Limited (Hong Kong, People's Republic of China) that has completed one phase-II trial (NCT05274802).Staphyloxanthin is a golden colored carotenoid with antioxidant activity that helps to neutralize reactive oxygen species (ROS) secreted by neutrophils, which protects bacteria [316,317].ALS4 is an inhibitor of 4,4ʹ-diapophytoene desaturase (CrtN), which is an enzyme involved in the biosynthesis of staphyloxanthin; however, although the structure of ALS4 has not been publicly disclosed, it is likely to be related to NP16 [318,319].

β-Lactam/β-lactamase Inhibitor (BL/BLI) Combinations Undergoing Clinical Evaluation
The discovery of the Streptomyces-derived BLI clavulanic acid was a significant breakthrough that rescued the use of many BL antibiotics by inactivating enzymes responsible for their destruction.There have been four new BL/BLI combinations approved since 2014 (Table 1): Zerbaxa in 2014 (contains a new cephalosporin, ceftolozane), Avycaz in 2015 (contains a new DBO-type BLI, avibactam), Vabomere in 2017 (contains a new boronate-type BLI, vaborbactam), and Recarbrio in 2019 (contains a new DBOtype BLI, relebactam), but no new combinations were approved from 2019-2022.In this section, ten new BL/BLI combinations are currently being evaluated in clinical trials or under an NDA/MAA filing are discussed (Table 6, Figs.11-13).It should be noted that BL/BLI combinations usually move straight from phase-I into phase-III trials.
Enmetazobactam (63) (AAI 101; IV) is a clavulanic acidtype BLI with a structure closely related to tazobactam with a methyl substituent on the tazobactam triazole ring.It has activity against ESBLs and some class A and D carbapenemases [335][336][337], and is being developed by Allecra Therapeutics (Weil am Rhein, Germany and Saint Louis, France).A combination of 63 and the cephalosporin cefepime (41) completed a phase-III trial (NCT03687255) in February 2020 for cUTI using IV administration, and successfully met criteria for non-inferiority, as well as superiority to piperacillintazobactam with respect to the primary efficacy outcome of clinical cure and microbiological eradication [338].Allecra Therapeutics is planning to submit an MAA in Europe, followed by an NDA in the USA.

Compounds discontinued from clinical development
Compounds and BL/BLI combinations that have been discontinued from clinical development or appear to have had their development halted since the 2019 review [25] are listed in Table 7 with notes indicating any known reasons for their failure or lack of progress.
While there was a similar number of compounds in the different development phases in 2011, 2013 and 2015 analyses (except for a reduced number in phase-III trials in 2011 (6) compared to 2013 (16) and 2015 (15)), the number in phase-I trials increased to 22 in 2019 [23] from an average of 12 compounds in 2011-2015 [24][25][26], and this was even higher at 26 in 2022 (Fig. 15).The number of compounds in phase-II also increased (from 18 in 2019 to 25 in 2022), reflecting the successful progression of several of the 2019 phase-I candidates and the entry of new antibacterials.At least 18 of the 26 phase-I compounds target G-ve bacteria (11 traditional compounds, one anti-virulence and six BLI combinations), with four of these also possessing G+ve activity, while there are an additional eight with G+ve only activity (six against TB and two against MRSA).While the overall numbers are still low compared to other therapeutic disease indications, the clinical pipeline is now starting to resemble the more traditional progression of attrition, rather than the flat or inverse progressions seen in 2011 [26], 2013 [25] and 2015 [24], and this likely reflects the success of push incentives driving innovative antibiotic discovery [6][7][8][9][10].

New antibacterial pharmacophore analysis
A pharmacophore is the common subunit of active molecules that interact with biological targets.It is crucial to develop new antibacterial drugs with new MoA and/or pharmacophores to slow down drug resistance and to potentially allow the identification of new combination therapies.This is also why there is considerable excitement around the potential of non-traditional antibacterials, along with the yet-to-be-proven hypothesis that some modalities, such as antivirulence strategies, will not lead to resistance since bacterial survival is not directly targeted [17,18,20,21].
The (fluoro)quinolone class are DNA synthesis inhibitors (DNA gyrase GyrA and topoisomerase IV parC [201]) that  are routinely used in clinical practice, while novobiocin, which is a DNA gyrase GyrB and topoisomerase IV ParE inhibitor, was briefly used as an antibacterial over 50 ago [201,368].BWC0977 (52) belongs to a new antibacterial class and equally inhibits both DNA gyrase GyrA and topoisomerase IV.Fobrepodacin ( 32) is an 'ethyl urea benzimidazole' that also binds to both GyrB and ParE, gepotidacin (10) inhibits GyrA at a different binding site to the quinolones, and zoliflodacin (11) inhibits GyrB.Ibezapolstat (27) is the first member of the dichlorobenzyl guanine class that inhibits DNA polymerase IIIC, while MGB-BP-3 ( 16) is a DNA minor groove binder.Bacterial protein synthesis inhibition can be caused by several compound classes including macrolides, aminoglycosides, tetracyclines, lincosamides, chloramphenicol, oxazolidinones, pleuromutilins and fusidic acid.There are two oxaborole-type leucine tRNA synthetase (LeuRS) inhibitors, epetraborole (13) and GSK3036656 (52), and one methionyl-tRNA synthetase inhibitor, CRS3123 (28), in clinical trials.The only marketed inhibitor of a tRNA synthetase is mupirocin, which targets isoleucyl-tRNA synthetase.
There are two direct-acting traditional and five nontraditional antibacterial compounds with new mechanisms.Telacebec ( 31) is an inhibitor of the mycobacterial respiratory cytochrome bc 1 complex [185,186,369].Inhibition of bacterial respiratory systems is an emerging MoA [369,370] with three bedaquiline analogs, sudapyridine (38), TBAJ-876 (55) and TBAJ-587 (56) that are also in clinical development.GSK2556286 (57) was recently disclosed to be an adenylyl cyclase Rv1625c agonist, which interferes with cholesterol catabolism and reduces the levels of this critical carbon source [304].RG6006 is a new antibacterial class but there is only limited public information available about the structure and MoA.There are three antivirulence compounds that employ totally different anti-virulence mechanisms: fluorothyazinone (40) inhibits the G-ve type III secretion system, GSK3882347 inhibits the binding of E. coli to host cell walls via FimH and ALS4 inhibits 4,4ʹ-diapophytoene desaturase (CrtN), which is an enzyme involved in the biosynthesis of staphyloxanthin.Finally, BVL-GSK098 (58) inactivates the TetR-like repressor, which reduces resistance to the TB drug ethionamide (59) and rescues its activity, which is conceptually similar to how BLIs restore the activity of BL antibiotics.

Administration analysis
The administration routes (po, oral; IV/po, intravenous oral switch; IV, intravenous; IV/topical, IV and topical; po topical, CDI oral; topical; inhalation; n/d, not disclosed) of

(34)
Fig. 17 Comparison of the numbers of novel antibacterial pharmacophores undergoing clinical development in 2011 [26], 2013 [25], 2015 [24], 2019 [23] and 2022 by development phase the small molecule antibacterial compounds under clinical development were analyzed by development phase (Fig. S1) and lead source (Fig. S1).Oral administration predominates and 19 of the 30 (~63%) are being against mycobacteria, which is pivotal as anti-TB drug combinations are taken for multiple months and are often administered in countries with limited capacity to deliver IV treatments.The second highest category is IV administration with 15, while there are four candidates that can be used both IV and po and two for both IV and topical.This IV/oral switch strategy is a competitive advantage as it can be implemented when patients move from hospital-based IV administration to oral administration in wards or at home.Four candidates are being trialed using the po topical administration route, which is used to treat gastrointestinal infections, such as C. difficile and H. pylori.For these infections, drugs are usually orally administered, but most are not significantly systemically absorbed, which reduces the potential for toxicity; however, one of the CDI clinical candidates, DNV-3837 ( 25) is being investigated using IV administration.There are four topically-only administered candidates, while murepavadin ( 49) is being trialed with inhaled administration to treat P. aeruginosa infections in the lungs of cystic fibrosis patients.This is being undertaken to more efficiently deliver 49 into the lungs, but it may also ameliorate kidney toxicity that was observed in a prior nosocomial pneumonia trial [273].

Conclusion and outlook
The shape of the antibacterial pipeline has changed since our first analysis in 2011 [26].At the front-end of the pipeline, there are now more than double the number of phase-I candidates (26) compared to 11 in 2015 [24] (Fig. 15).Funding initiatives have also helped to boost the number of phase-II (25) compounds since 2019 (18) (Fig. 15).Encouragingly, 16/26 (62%) of the compounds in phase-I and 14/25 (56%) in phase-II contain new pharmacophores (Figs.16 and 17), with some also having new MoA (Table 8).Small molecule non-traditional antibacterial candidates are also starting to move through the pipeline with five in active development: fluorothyazinone (40), dovramilast (42), BVL-GSK098 (58), GSK3882347 and ALS4.Due to the increasing number of compounds with novel pharmacophores and targets in the pipeline (Table 8, Figs.16 and 17), it is more likely that novel antibacterial drug classes will enter the clinic in the next few years, which is preferable to just expanding the pool of 'me-too' antibiotics.However, despite these early stage improvements, it is sobering to note that the overall antibacterial pipeline is still sparse compared to other therapeutic indications such as oncology (2,335 clinical trials in 2021 [371]) and even COVID-19 vaccines (180 in the pipeline in February 2023 [372]).
In contrast to the early-stage pipeline, the late-stage pipeline is still experiencing issues.There were only two new small molecule antibacterial drugs first approved between 2020 and 2022 (Table 1, Fig. 2): the fluoroquinolone levonadifloxacin (1) and its prodrug 2 in India in 2020 and the oxazolidinone contezolid (4) in China in 2021.There was also one 'non-traditional' live biotherapeutic product, Rebyota, approved in the USA in 2022 (Table 2).The last first-in-class small molecule approval was the anti-TB diarylquinoline bedaquiline in 2012.However, this could change, if the current phase-III candidates, gepotidacin (10), zoliflodacin (11) and epetraborole (13) (Table 3, Fig. 4), all of which have new pharmacophores, were granted approval to treat gonorrhea and G-ve bacteria, gonorrhea, and M. avium complex (MAC) infections respectively.A future approval of the durlobactam (60) + sulbactam (61) combination for the treatment of A. baumannii-calcoaceticus (ABC) complex infections would also be a welcome addition to the antibacterial armamentarium.There has also been a steady but small decline in the number of phase-III candidates from 2013 to 2022 (Fig. 15).It will be critical to monitor how many of the phase-I and -II candidates, especially the compounds with new pharmacophores, move into Phase-III and beyond in the next few years.
In addition to the difficulty in identifying novel lead compounds suitable for antibacterial drug development, the ability to secure funding for phase-III trials and NDA/ MAAs, as well as the capacity to generate adequate revenue to get positive net returns on investment for marketed antibacterial drugs [2][3][4][5], have been major obstacles to antibacterial drug development.Hopefully funding from organizations such as the AMR Action Fund [9,10] will help to ameliorate some of these funding issues, while the successful implementation of pull initiatives should help to improve financial returns [11][12][13][14][15][16].Another welcome addition has been the US FDA's Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD) pathway that provides the potential for smaller, shorter, or fewer clinical trials (at least two phase-III trials are usually required) if the antibacterial drug candidate is "intended to treat a serious or life-threatening infection in a limited population of patients with unmet needs" [373].However, the approved drug then carries a label restricting its use, which could limit future sales.
At least 19/26 (73%) phase-I compounds target G-ve bacteria (12 traditional compounds, one anti-virulence and six BL/BLI combinations), with four of these also possessing anti-G+ve activity.The high percentage of G-ve candidates being developed mirrors the clinical need and the recent focus of most funding schemes; however, the addition of G+ve activity to the 2022/23 CARB-X funding calls reflects the high mortality observed for global G+ve resistant infections in 2019 [1].Only six of these 17 traditional G-ve antibacterial candidates are administered with four of these being BL/BLI prodrugs.Although NPs have traditionally been the main source of novel antibacterials, 23 of the 34 (68%) of the compounds with new antibacterial pharmacophores were synthetically derived.There are also a substantial number of antitubercular drugs (TB and NTM) in the pipeline (19/62 (31%); one in phase-III, 12 in phase-II, and six in phase-I), showing the success of targeted funding for neglected diseases through organizations such as the TB Alliance (New York, NY, USA) and the Bill & Melinda Gates Foundation (Seattle, WA, USA).
In conclusion, despite the encouraging trends in phase-I and -II antibacterial drug candidates and plans to address issues with the late-stage pipeline, it is not the time to relax the urgency to continue to stimulate further antibacterial drug discovery and development.

Fig. 8
Fig.8Structures of NP and peptide-derived compounds in phase-I clinical trials (Table5)

Table 2
CDI C. difficile infection, G+ve Gram-positive bacteria, mAb monoclonal antibody, USA United States of America

Table 3
Antibiotics with NDA/MAA submitted or in phase-III clinical trials (structures in Figs.3 and 4) CABP community-acquired bacterial pneumonia, cIAI complicated intra-abdominal infections, cUTI complicated urinary tract infections, IV intravenous, NP natural product, PBP penicillin binding protein, po per orem (oral), NTM non-tuberculosis mycobacteria, S synthetic, uUTI uncomplicated urinary tract infections, UTI urinary tract infections a Compounds with new pharmacophores and MoA are underlined

Table 7
[23]ounds discontinued or likely to have been discontinued from clinical development since 2018 the previous review[23]

Table 8
New antibacterial pharmacophores, separated into major MoA classes, including compound name, phase, antibacterial class, lead source, activity, MoA and administration