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Using large-scale, systems biology approaches, we can now systematically map synergistic and antagonistic interactions between drugs. Consequently, drug antagonism is providing us with insight into the functions and relatedness of cellular components, mechanisms of drug action and novel ways to inhibit the evolution of antibiotic resistance.

Overexpression of a drug’s molecular target increases drug resistance in some cases. Here the authors show that overexpressing antibiotic targets in Escherichia colican cause positive and negative changes in drug resistance, depending on whether the drug induces harmful reactions involving its target.

New data from a large healthcare organization in Israel reveal a reduction in new infections in an unvaccinated population in communities with rapid vaccination rollouts, suggesting that mass vaccination strategies confer cross-protection of unvaccinated individuals.

Vaccination with BNT162b2 is associated with lower viral load in breakthrough infections of SARS-CoV-2, but this effect wanes at 2 months and vanishes at 6 months after vaccination. A third vaccine dose—or booster—restores the reduction in viral load.

Breakthrough infections of SARS-CoV-2 occurring 12 or more days after the first dose of the BNT162b2 mRNA vaccine were associated with lower viral loads than those found in unvaccinated individuals, suggesting that the vaccine might reduce infectiousness.

Roy Kishony and colleagues sequenced the genomes of Burkholderia dolosa isolates from patients with cystic fibrosis, using colony resequencing and deep population sequencing approaches to allow comparisons of multiple isolates from each individual. They identify extensive intrastrain genomic diversity and show specific signatures of selection acting on the pathogen within individual patients.

Roy Kishony and colleagues sequenced the genomes of 112 Burkholderia dolosa isolates recovered from 14 individuals with cystic fibrosis as part of a retrospective study from a hospital epidemic monitored over the course of 16 years. They tracked recurrent mutations occurring in the bacterial isolates and found that 17 genes showed evidence of parallel adaptive evolution.

Roy Kishony and colleagues develop a device for the continuous culture of bacterial populations under constant antibiotic selection pressure. They use this morbidostat, together with whole-genome sequencing of E. coli strains, to follow evolutionary paths leading to high levels of resistance to three individual drugs.

The BNT162b2 COVID-19 vaccine has been shown to reduce viral load of breakthrough infections (BTIs). Here, analyzing viral loads of BTIs post third vaccine shot, Levine-Tiefenbrun et al. show waning of the booster’s effectiveness in reducing infectiousness within months, mirroring the rate and magnitude of decline observed post the second shot.

A major challenge of theoretical ecology is explaining the stable coexistence of diverse multi-species communities. Here, the authors show that when the interactions among two species depend on the presence of other species, the diversity of the community becomes a necessity rather than an obstacle for its stability.

On the basis of the personalized data of over 300,000 individuals with urinary tract infections, a machine-learning algorithm can help select an antibiotic for treatment of a urinary tract infection to which the infecting pathogen is not already resistant.

The authors sequence the genomes of 552 bacterial isolates sampled across 23 sites of the lungs of a patient with cystic fibrosis, and identify bacterial genes under global and location-specific adaptation.

It remains unclear how rapid antibiotic switching affects the evolution of antibiotic resistance in individual patients. Here, Chung et al. combine short- and long-read sequencing and resistance phenotyping of 420 serial isolates of Pseudomonas aeruginosa collected from the onset of respiratory infection, and show that rare resistance mutations can increase by nearly 40-fold over 5–12 days in response to antibiotic changes, while mutations conferring resistance to antibiotics not administered diminish and even go to extinction.

Beta-lactam antibiotics and beta-lactamase inhibitors compete for the same binding site on beta-lactamases; thus, mutations that increase beta-lactamase activity likely increase also susceptibility to the inhibitor. Here, Russ et al. identify rare mutations in the ampC beta-lactamase gene that escape this adaptive tradeoff specifically for certain drug combinations.

Although tetracycline selects for tetracycline-resistant bacterial strains, degradation products of tetracycline are now shown to select for tetracycline-sensitive strains, providing a potential mechanism for the observed coexistence of antibiotic-sensitive and antibiotic-resistant bacteria in the environment.

The authors review new tools for studying the evolution of antibiotic resistance, including approaches to evolve resistance in the laboratory and analysis of clinical samples. Insights into pathways of evolution and the basis of resistance could inform future management of infections.

Bacteria evolving within humans employ strategies to overcome trade-offs. Here, the authors report that the cystic fibrosis-associated pathogen Burkholderia dolosa alternates phenotypes in vivo by accumulating successive de novo mutations.

Bacteria and their viruses coexist and coevolve in nature, but maintaining them together in the lab is challenging. Here, a spatially structured environment allowed prolonged coevolution, with bacteria and phage diversifying into multiple ecotypes, uncovering gene mechanisms affecting phage-bacteria interactions.

Staphylococcus epidermidis is a widespread early colonizer in the neonatal skin and a cause of hospital-acquired infections. Here, using whole-genome sequencing of 632 cultured S. epidermidis isolates derived from premature infants, the authors characterize the spatiotemporally strain-level genomic variability, finding patient-specific colonization signatures and a fast gain and loss of the antibiotic resistance gene mecA via the evolution of genotypically diverse structural variants.

The mecA gene confers resistance to many β-lactam antibiotics in community-associated MRSA bacteria. Here, Snitser et al. show that mecA also provides broad selective advantage across diverse chemical environments in the presence of subinhibitory β-lactam concentrations, by protecting the bacteria against increased cell-envelope permeability.

Genomic analysis of Mycobacterium tuberculosis in postmortem biopsies provides a window into intrahost diversification of a disseminated pathogen.

Bacterial resistance to beta-lactam antibiotics is on the rise, but laboratory evolution studies do not always recapitulate clinical resistance levels. Here, the authors select Escherichia coli mutants with varying degrees of beta-lactam resistance, showing that combinations of distinct genetic mutations, accessible at large population sizes, can drive high-level resistance independently of beta-lactamases.

In the debate about how bacterial mutations arise, an experiment in 1943 showed that they can occur spontaneously and independently of a selection pressure. This study also popularized the use of maths-driven analysis of biological data.

The increasing levels of antibiotic resistance observed in clinical isolates, coupled with a lack of new drugs coming through the development pipeline, make the problem of antibiotic resistance a global crisis. In this Essay, Davies and colleagues draw up a priority list of urgent steps and future research directions that are needed to tackle this growing problem.

Antibiotics promote the spread of resistance in the clinic, but various mechanisms may exist in natural environments that tilt the balance toward antibiotic sensitivity. Studying such mechanisms could help us understand the evolutionary dynamics of resistance and sensitivity in the wild, which may inspire new therapeutic strategies.

Antibiotic resistance can evolve through the stepwise accumulation of mutations. Here, the authors reconstruct the multistep evolutionary pathway for trimethoprim resistance and show that epistatic interactions increase rather than decrease the accessibility of each adaptive peak.

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.

Different pairs of antibiotics show qualitatively different bacterial clearance interactions—some pairs show reciprocal suppression whereby the drug mixture efficacy is weaker than the individual drugs alone, and the clearance efficacy decreases as more drugs are added.

Clinicians have long observed that infections diagnosed as susceptible to antibiotics can sometimes resist treatment. New studies show that such treatment failures can be explained by subpopulations of transiently resistant cells that are often missed by standard clinical diagnostics, offering new therapeutic avenues.

Patients in intensive care units administered a bacterial probiotic had an elevated risk of bloodstream infection due to the probiotic strain.

Intermediate colistin production in E. coli maximizes the benefit of inhibiting sensitive neighbours while minimizing competition from resistant cheaters.

Mathematical modelling and simulations reveal that including antibiotic degraders in ecological models of microbial species interaction allows the system to robustly move towards an intermixed stable state, more representative of real-world observations.

A high-throughput screen against the E. coli tetracycline-resistance efflux pump TetA identifies two ‘selection-inverting’ compounds that swap tetracycline resistance for resistance to another antibiotic, paving the way for two-phase antibiotic treatment protocols.

In vitro evolution experiments on haploid, diploid, and tetraploid yeast strains show that adaptation is faster in tetraploids, providing direct quantitative evidence that in some environments polyploidy can accelerate evolutionary adaptation.