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 difficile infection (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 nontoxigenic C. 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 of Helicobacter 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. pylori to date and highlights some future trends in this area.
In this Review, Wagenlehner et 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 nasal commensal bacterium Staphylococcus lugdunensis produces a novel cyclic peptide antibiotic, lugdunin, that inhibits colonization by S. aureus in animal models and is associated with a significantly reduced S. aureus carriage rate in humans, suggesting that human commensal bacteria could be a valuable resource for the discovery of new antibiotics.
Antibiotic resistance is common in environmental bacteria, including those living in isolated caves. Here, Pawlowski et 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.
The bicyclic azetidines, a class of potent, well-tolerated antimalarial compounds that is active against multiple stages of the Plasmodium life-cycle, has been discovered following screens against libraries of compounds reminiscent of natural products.
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 MRSA, are proving increasingly difficult to treat; here, one reason for this is confirmed to be the fact that S. aureus bacteria can reside in intracellular reservoirs where they are protected from antibiotics, but a new strategy—based on an antibody–antibiotic conjugate—can specifically target these reservoirs.
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.
From a new species of β-proteobacteria, an antibiotic called teixobactin that does not generate resistance has been characterized; the antibiotic has two different lipid targets in different bacterial cell wall synthesis components, which may explain why resistance was not observed.
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.
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, is identified and characterized here; the compound iKIX1 inhibits Pdr1-mediated gene activation and resensitizes drug-resistant C. glabrata to azole antifungals in vitro and in animal models of disseminated and urinary tract infection.
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.
The description of a compound (DDD107498) with antimalarial activity against multiple life-cycle stages of Plasmodium falciparum and good pharmacokinetic and safety properties, with potential for single-dose treatment, chemoprotection and prevention of transmission.
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. glabrata clinical 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.
An analysis of bacterial community structure and antibiotic resistance gene content of interconnected human faecal and environmental samples from two low-income communities in Latin America was carried out using a combination of functional metagenomics, 16S sequencing and shotgun sequencing; resistomes across habitats are generally structured along ecological gradients, but key resistance genes can cross these boundaries, and the authors assessed the usefulness of excreta management protocols in the prevention of resistance gene dissemination.
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.