Journal Article

The population genetics of antibiotic resistance: integrating molecular mechanisms and treatment contexts

Hall, Alex R., Buckling, Angus, MacLean, R. Craig, Perron, Gabriel G.

2010

Overview

Key Points The fitness effects of antibiotic-resistance mutations and of mutations that compensate for the cost of resistance depends on the molecular basis of resistance and the ecological (or treatment) context in which resistance evolves. The distribution of fitness effects of resistance mutations is determined by antibiotic dose and drug–target interactions. Resistance mutations impose a fitness cost that varies widely among mutations. It may be possible to predict costs of resistance by considering the effects of resistance mutations on protein stability. Compensatory mutations alleviate the cost of resistance, allowing resistant strains to persist in the absence of antibiotics. The opportunity for compensation varies among resistant mutants and it may be possible to predict this variability by explicitly considering the mechanistic basis of the costs of resistance. Physiological interactions between antibiotics and genetic interactions between resistance mutations are crucial for the evolution of multidrug resistance by modifying the benefits associated with resistance and compensatory mutation. Immigration from antibiotic-free populations is important in the evolution of resistance. Immigration accelerates the evolution of resistance when resistance mutations are rare and immigration can reverse resistance following the cessation of antibiotic use. Spatial and temporal patterns of antibiotic use play a key part in the evolution of resistance. Resistance evolves most slowly under maximal levels of environmental heterogeneity. Future work should concentrate on developing predictive models of resistance evolution by integrating molecular mechanisms of resistance with treatment context. This may help develop improved treatment strategies for preventing resistance evolution in pathogen populations. The authors discuss the evolutionary dynamics of antibiotic resistance in bacteria in relation to the complex interplay between population genetic factors and the spatial and temporal pattern of antibiotic use. Despite efforts from a range of disciplines, our ability to predict and combat the evolution of antibiotic resistance in pathogenic bacteria is limited. This is because resistance evolution involves a complex interplay between the specific drug, bacterial genetics and both natural and treatment ecology. Incorporating details of the molecular mechanisms of drug resistance and ecology into evolutionary models has proved useful in predicting the dynamics of resistance evolution. However, putting these models to practical use will require extensive collaboration between mathematicians, molecular biologists, evolutionary ecologists and clinicians.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/181/2475 / 631/208/457 / 631/326/41/1969/2038 / 692/700/565/1436/2774 / Agriculture / Animal Genetics and Genomics / Animals / Anti-Bacterial Agents - chemical synthesis / Anti-Bacterial Agents - therapeutic use / Antibiotics / Bacteria / Bacterial Infections - drug therapy / Bacterial Infections - genetics / Bacterial Infections - microbiology / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Drug dosages / Drug resistance / Drug resistance in microorganisms / Drug Resistance, Bacterial - genetics / Ecology / Evolution / Evolution, Molecular / Evolutionary biology / Fundamental and applied biological sciences. Psychology / Gene Function / Gene mutations / Genetic aspects / Genetics of eukaryotes. Biological and molecular evolution / Genetics, Population - trends / Human Genetics / Humans / Models, Biological / Mutation / Pathogens / Population genetics / Proteins / review-article / Signal Transduction - genetics / Systems Integration