Drug resistance is threatening to sideline the currently available antibiotics, and new antibiotics are unlikely to become available before the current arsenal becomes ineffective. Brown proposes the use of approved drugs or neutraceuticals as antibiotic resistance breakers — compounds that could be administered alongside current antibiotics to prolong their useful lifespan — to bridge the gap.
Resistance to antimicrobials is a global problem of increasing importance. Pathogens rapidly develop mutations that render current treatments ineffective. For example, resistance to carbapenems, one of the ‘last lines’ of antibiotics, is widespread and has been observed in numerous countries; resistance to artemisinin, the gold standard in malaria treatment, has also emerged. Our current arsenal of antimicrobial agents thus has a limited lifespan and new drugs are urgently needed. Tackling this resistance will require a deep understanding of microbial infections and the mechanisms through which resistance arises, as well as concerted efforts between academia and industry aimed at developing novel antimicrobial agents.
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The failure of antibiotics can arise by different bacterial survival strategies, each with implications for treatment. In this Opinion article, Balaban and colleagues propose a new experimental framework for distinguishing between several forms of resistance, tolerance and persistence to antibiotic treatment.
Infection with HIV-1 is currently incurable as HIV-1 can persist as integrated provirus in the genome of latently infected CD4+T cells, where it is invisible to the immune system and not responsive to drugs. Here, Ferrari and colleagues discuss the development of novel engineered bispecific and trispecific antibodies, particularly dual-affinity re-targeting (DART) proteins, designed to eradicate latently infected cells.
Microorganisms produce a wealth of structurally diverse specialized metabolites with great potential for use in medicine and agriculture. In this Review, Rutledge and Challis provide an overview of the approaches that are available to identify and activate cryptic microbial biosynthetic gene clusters, which represent an untapped reservoir of useful metabolites.
Here, the authors detail our current understanding of specialized pro-resolving mediators (SPMs), a family of endogenous mediators that have important roles in promoting the resolution of inflammation. With a focus on the lungs, they discuss the contribution of SPMs to infectious and chronic inflammatory diseases and their emerging therapeutic potential.
Incentives are increasingly available for the development of new drugs to tackle antibiotic resistance, but major scientific challenges remain, such as achieving penetration into bacteria. Tommasi and colleagues describe AstraZeneca's experiences in antibacterial drug discovery over the past decade using both target-based and phenotypic screening approaches, and discuss the reasons for failure as well as strategies to improve cytoplasmic penetration.
Clostridium difficileinfection (CDI) is one of the most common health-care-associated infections. Here, Kociolek and Gerding discuss the latest advances in the treatment and prevention of CDI, describing developments in antibiotic therapy, biotherapeutic approaches such as faecal microbiota transplantation or nontoxigenicC. difficile, and immunological approaches such as antibodies or vaccines.
Antibiotic-resistant bacteria are causing a global health crisis. Here, the authors review recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics. This information should aid the discovery and development of new compounds that can circumvent or neutralize existing resistance mechanisms.
Treatment of HCV infection has evolved rapidly with the development of effective direct-acting antiviral agents (DAAs) that target different stages in the viral life cycle. Here, Götte and Feld describe the mechanisms of action of these DAAs and the different clinical attributes of each drug class (such as barriers to resistance, drug–drug interactions). Challenges in drug development efforts for the future are also briefly discussed.
Tuberculosis (TB) is an airborne infectious disease with high morbidity and mortality rates, especially in low-income countries. Advances in diagnosis and treatment have been made, but new vaccines and drugs are needed to achieve the goal of the End TB Strategy by 2035.
Despite considerable advances in malaria medicines in the past 20 years, the global burden of malaria remains substantial. Moreover, continued emergence of drug resistance ensures that new antimalarials will be needed in the near future. Wells and colleagues summarize the current landscape of antimalarial therapies and investigational drugs, highlighting the progress made, identifying gaps in terms of target profiles and recommending priorities for future research.
Urinary tract infections (UTIs) are very common and are a major contributor to global antibiotic use and resistance. Without effective antibiotics active against common uropathogens, many urological procedures would carry excessive risk. In this article, Zowawi and coauthors describe the current global epidemiology of resistance in Gram-negative uropathogens and discuss the genetic and molecular mechanisms underlying the resistance of these phenotypes. They also examine the effect of resistance on common urological procedures and summarize various preventive and therapeutic options.
Bacteria are frequently exposed to subinhibitory concentrations of antibiotics, and recent evidence suggests that this is likely to select for resistance. In this Review, Andersson and Hughes discuss the ecology of antibiotics, the ability of subinhibitory concentrations of antibiotics to select for resistance and the effects of low-level drug exposure on bacterial physiology.
The quality of the chemical starting points for small-molecule drug discovery is a key factor in improving the likelihood of clinical success. In this article, experts from several organizations involved in drug discovery for malaria, tuberculosis and neglected tropical diseases present disease-specific criteria for hits and leads, and discuss the underlying rationale.
The discovery ofHelicobacter pylori redirected our understanding of certain gastroduodenal diseases. Many of these diseases (such as ulcer disease and mucosal associated lymphoid tissue lymphoma) have become curable, and others (gastric cancer) might be preventable with the application of H. pylori eradication therapy. This Timeline gives an overview of the success of clinical research on H. pylorito date and highlights some future trends in this area.
In this Review, Wagenlehneret al. discuss strategies to reduce rates of severe symptomatic infection and urosepsis after prostate biopsy, such as preoperative assessment (including history of fluoroquinolone intake over the past 6 months), urine culture, targeted antibiotic prophylaxis after sampling of the rectal flora, bowel preparation, and perineal prostate biopsy.
Severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), which are caused by coronaviruses, have attracted substantial attention owing to their high mortality rates and potential to cause epidemics. Yuen and colleagues discuss progress with treatment options for these syndromes, including virus- and host-targeted drugs, and the challenges that need to be overcome in their further development.
Evolutionary consequences of drug resistance: shared principles across diverse targets and organisms
The emergence of drug resistance is a major challenge for controlling diverse infectious diseases and cancer. In this Review, the authors discuss the mechanisms and evolutionary consequences of drug resistance. They highlight commonalities and distinctions across diverse pathogens and systems, and the implications for optimizing the current use and future development of drug therapies.
The majority of systemic bacterial infections are caused by endogenous pathogens from human microbiota, and the opportunistic pathogen Staphylococcus aureus, commonly found in the external opening of the nostrils, is one of the most clinically important because of the prevalence of multi-drug resistant strains. The mechanisms that permit or interfere with pathogen colonization have remained unclear. This study shows that S. lugdunensis, a commensal bacterium that shares the nasal niche with S. aureus and is associated with a reduced S. aureus carriage rate in humans, produces a novel cyclic peptide antibiotic (lugdunin) that inhibits colonization by S. aureus in animal models. Lugdunin is bactericidal against major pathogens and not prone to causing development of resistance in S. aureus, suggesting that lugdunin or lugdunin-producing commensals could be valuable for preventing staphylococcal infections.
Antibiotic resistance is common in environmental bacteria, including those living in isolated caves. Here, Pawlowskiet al. study one of these bacterial strains, showing that it is resistant to most clinically used antibiotics through a remarkable variety of mechanisms, some of which are new to science.
Antimalarial drugs have thus far been mainly derived from natural products and synthetic 'drug-like' compounds. This study describes the discovery, following screens against libraries of compounds reminiscent of natural products, of promising small molecules that are highly active against the malaria parasite. Of particular interest is a series of bicyclic azetidines that inhibit a novel malaria target, phenylalanine tRNA–ligase. The bicyclic azetidines can cure mice from all life stages of the Plasmodium parasite with a single low-dose in different mouse infection assays, including a humanized mouse model of malaria liver-stage disease. These compounds have the potential to cure and prevent transmission of the disease in a single oral exposure.
It is unclear whether new antimalarial compounds may rapidly lose effectiveness in the field because of parasite resistance. Here, Corey et al.investigate the acquisition of drug resistance and the extent to which common resistance mechanisms decrease susceptibility to a diverse set of 50 antimalarial compounds.
Antibiotic-resistant strains of Staphylococcus aureus, such as methicillin-resistant S. aureus (MRSA), are proving increasingly difficult to treat. This study confirms that one reason for this is the ability of the pathogen to reside in intracellular reservoirs where they are protected from antibiotics. To counter this barrier, the authors develop a new strategy — based on an antibody–antibiotic conjugate (AAC) — to specifically target these reservoirs. The antibody binds to wall teichoic acids on the surface of S. aureus cells, and internalization of AAC-opsonized bacteria by host cells results in removal by host proteases of the linker between the antibody and the antibiotic, thereby releasing the antibiotic in its active form. A single dose of AAC is effective in a mouse model of bacteraemia, and is superior to the use of vancomycin, the current standard of care for MRSA infection. These findings are a proof-of-principle for the possibility of using antibody carriers to deliver existing antibiotics in a way that could ensure their continued clinical success.
An undetected, phenotypically colistin-resistant subpopulation of Enterobacter cloacae mediates antibiotic treatment failure
Dietary zinc supplements are in common use, but their effect on infection is unclear. New findings now show that excess dietary zinc reduces the diversity of the gut microbiota and increases the susceptibility of antibiotic-treated mice to Clostridium difficile infection.
Coupling the specificity of CRISPR-Cas nucleases and bacteriophage delivery enables exquisitely precise bacterial killing.
MALDI mass spectrometry shows distinct patterns of drug distribution in tuberculosis lesions in human lungs that provide insight into treatment efficacy.
A series of synthetic lethal strategies identifies a small-molecule inhibitor of Staphylococcus aureus DltB, links teichoic acid D-alanylation to virulence and identifies synergistic antibiotic drug combinations.
Globally prevalent PfMDR1 mutations modulate Plasmodium falciparum susceptibility to artemisinin-based combination therapies
Antimalarial chemotherapy relies on combination therapies (ACTs) consisting of an artemisinin derivative and a partner drug. Here, the authors study the effects of globally prevalent mutations in a multidrug resistance transporter (PfMDR1) on the parasite’s susceptibility to ACT drugs.
Emergence of scarlet fever Streptococcus pyogenes emm12 clones in Hong Kong is associated with toxin acquisition and multidrug resistance
Mark Walker and colleagues report the whole-genome sequencing of 132 group A Streptococcus (GAS) isolates of a sequence type that has been associated with scarlet fever. The isolates were obtained from 58 clinical cases of scarlet fever and 83 cases without scarlet fever during the course of a recent epidemic in Hong Kong.
Directed evolution of a recombinase that excises the provirus of most HIV-1 primary isolates with high specificity
Excision of integrated HIV proviruses derived from most HIV-1 strains is achieved with a recombinase evolved in vitro.
Most antibiotics in clinical use were discovered by screening cultivable soil microorganisms, a much depleted resource that has not been adequately replaced by synthetic approaches. Hence the widespread alarm at the spread of antibiotic resistance. This paper presents some welcome good news, in the form of the isolation and characterization of a new antibiotic active against a range of bacterial pathogens including Staphylococcus aureus, and apparently untroubled by the evolution of resistance. Kim Lewis and colleagues use a recently developed system for in situ cultivation of previously uncultured soil bacteria and identify a β-proteobacterium, Eleftheria terrae sp. that produces a depsipeptide they call teixobactin. Teixobactin is active in vivo and separately targets precursors in the biosynthetic pathways for each of two major components of the bacterial cell wall, peptidoglycan and teichoic acid. Screens for mutants resistant teixobactin were negative, perhaps a consequence of this novel two-target mechanism.
Antibiotic-mediated selection may promote or suppress conjugation dynamics, dependent on the population structure, physiological status of cells and energy availability.
Rapid antibiotic-resistance predictions from genome sequence data for Staphylococcus aureus and Mycobacterium tuberculosis
The clinical application of new sequencing techniques is expected to accelerate pathogen identification. Here, Bradley et al. present a clinician-friendly software package that uses sequencing data for quick and accurate prediction of antibiotic resistance profiles for S. aureus and M. tuberculosis.
Delivery of CRISPR-Cas nucleases using bacteriophage enables targeted killing of microbes in a population
Andrew Koh and colleagues report that gut anaerobes in adult mice prevent Candida albicans colonization by inducing an antimicrobial peptide.
ATP depletion is associated with induction of antibiotic tolerance in Staphylococcus aureus.
Joy Nishikawa et al. report the identification and characterization of a small-molecule inhibitor of a protein–protein interaction between the transcription factor Pdr1 and the MED15 subunit of Mediator in the fungal pathogen Candida glabrata. The lead compound, iKIX1, inhibits Pdr1-mediated gene activation and re-sensitizes drug-resistant C. glabrata to azole antifungals in vitro and in animal models of disseminated and urinary tract infection. The NMR structure of the interaction between Mediator and Pdr1, has also improved our understanding of the mechanism of gene activation by Pdr1 and its inhibition by iKIX1.
Triple combinations of carbapenem, penicillin and β-lactamase inhibitor antibiotic classes are synergistic against MRSA through a mechanism involving allostery-based synergy and collateral sensitivity and can thus be applied at doses that lead to less resistance.
Francis Drobniewski and colleagues report the whole-genome sequencing of 1,000 Mycobacterium tuberculosis strains obtained prospectively from patients over a 2-year period in Samara, Russia, a region with a high incidence of multidrug-resistant (MDR) tuberculosis. They compare these strains to a diverse panel of strains isolated from across the UK and characterize the patterns of the emergence and evolution of drug resistance.
With artemisinin resistance spreading, there is an urgent need to develop new therapeutics to target Plasmodium falciparum, the causative agent of malaria. Here Ian Gilbert and colleagues report the discovery of a compound (DDD107498) with antimalarial activity against multiple life-cycle stages of the parasite and good pharmacokinetic and safety properties. It is non-mutagenic and has potential for both single-dose treatment and once-weekly chemoprotection. DDD107498 acts through inhibition of cytosolic protein synthesis, with translation elongation factor eEF2 as its target.
Epistatic interactions between neuraminidase mutations facilitated the emergence of the oseltamivir-resistant H1N1 influenza viruses
Understanding influenza evolution is challenging. Here, the authors determine the timing and order of critical amino acid changes that contributed to a world-wide predominance of oseltamivir-resistant H1N1 influenza viruses and show the role of epistasis in the emergence of novel influenza phenotypes.
Antibiotic therapy has varying effects on the species richness of the preterm infant gut microbiota, but can lead to a dominance of multi-drug resistant species and an enrichment of antibiotic resistance genes.
Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance
The fungal pathogen Candida glabrata readily acquires resistance to multiple types of antifungal drugs. Here, Healey et al. show that C. glabrataclinical isolates often carry mutations in a gene involved in DNA mismatch repair, and this is associated with increased propensity to develop antifungal resistance.
Frequency of antibiotic application drives rapid evolutionary adaptation of Escherichia coli persistence
Evolution of high levels of multidrug tolerance in E. coli occurs rapidly via single point mutations and adapts to drug treatment frequency. Conversely reversion in the absence of antibiotic treatment is slow and only partially effective.
Mapping the distribution and dissemination of antibiotic resistance genes is a public health priority. Gautam Dantas and colleagues have characterized the bacterial community structure and resistance gene exchange networks from two low-income Latin American communities — a rural village of subsistence farmers 35 km south of San Salvador, El Salvador and a shanty town in the desert hills about 15 km southwest of Lima, Peru. Using functional genomics and whole-metagenome sequencing of hundreds of interconnected human faecal and environmental samples, the authors find that resistomes across habitats are generally structured by bacterial phylogeny along ecological gradients, but that key resistance genes can cross these boundaries. They also assess the usefulness of excreta management protocols in the prevention of resistance gene dissemination. Collectively, this work lays the foundation for quantitative risk assessment and surveillance of antibiotic resistance gene transmission across diverse environments.
Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events
Vanessa Wong and colleagues report whole-genome sequencing of 1,832 Salmonella enterica serovar Typhi isolates from 63 endemic countries. They identify mutations that define the multidrug resistant (MDR) H58 lineage and report numerous inter- and intracontinental transmissions of this lineage as well as an ongoing MDR typhoid epidemic in Africa.
Antibiotic concentrations are low in most natural environments, except around localized antibiotic sources. Here, Chait et al.show that sub-inhibitory antibiotic levels can interact with many other stresses to generate complex patterns of selection for and against resistance to the antibiotic.
Genomic and functional analyses of Mycobacterium tuberculosis strains implicate ald in D-cycloserine resistance
Alexander Pym, Ashlee Earl and colleagues use the whole-genome sequences from 498 strains of Mycobacterium tuberculosis to identify new genotypes conferring resistance to antitubercular drugs. They find that loss-of-function mutations in ald (Rv2780), encoding L-alanine dehydrogenase, are associated with unexplained drug resistance and demonstrate that these mutations confer resistance to D-cycloserine.
As well as allowing horizontal gene transfer, the increased copy number of plasmids could accelerate evolution. Here, it is shown that clinically relevant antibiotic resistance evolves faster when the target gene is on a plasmid.
Plasmids facilitate the evolution of antibiotic resistance but little is known about bacteria–plasmid evolution. Here, the authors show that when bacteria adapt to one plasmid, they become generally permissive to plasmid carriage.
Mobile genetic elements can confer antibiotic resistance on their bacterial hosts. However, they are often costly leading to conflict with the host chromosome, which can drive intragenomic coevolution and consequent modulation of resistance.
Relationships between antibiotic interactions and diversity are often examined in ecologically stable in silico models, but building in biologically realistic features is found to promote coexistence and more diversity than idealized models.
The evolution of antibiotic resistance is expected to incur a cost. Here, the lack of an apparent cost during doxycycline resistance evolution is reconciled with evolutionary trade-off theory.
Successive alleles competing along predictable adaptive trajectories largely governs the rate of evolution of proteins involved in antimalarial drug resistance, with implications for management of antimicrobial resistance in the real world.