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

Nature Reviews Genetics volume 11, pages 405–414 (2010)Cite this article

Subjects

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.

Abstract

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.

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Acknowledgements

The authors acknowledge support from the European Research Council, the Royal Society and the Leverhulme Trust.

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Authors and Affiliations

  1. Department of Zoology, University of Oxford, OX1 3PS, Oxford, UK

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

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  1. R. Craig MacLean
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  2. Alex R. Hall
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Correspondence to R. Craig MacLean.

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DATABASES

TB Drug Resistance Mutation Database

FURTHER INFORMATION

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Glossary

Strong selection

Occurs when selection imposes strong pressure on the evolution of a trait. In the context of this Review, the strength of selection for resistance increases with antibiotic dose. Most experiments select for resistance under antibiotic doses that prevent growth of wild-type strains, implying strong selection for resistance.

Population bottlenecking

Occurs when the size of a population is reduced dramatically.

Effective population size

The effective population size of a population is the number of individuals in a theoretically ideal population that have the same magnitude of genetic drift as the actual population.

Extreme value theory

A branch of statistical theory that is concerned with the asymptotic properties of the largest samples from a probability distribution, that is those from the tail of the distribution.

Systems-based approach

An approach that investigates a biological phenomenon by assaying a wide range of levels of biological organization, from individual proteins to entire cellular networks. In the context of antibiotic resistance, such an approach involves predicting the fitness effects of resistance and compensatory mutations (ideally quantitatively) based on molecular models of resistance and compensation.

Pleiotropy

A phenomenon in which a gene can influence two or more independent characteristics.

Adaptive walks

A metaphor used to describe the sequence of fixation of beneficial mutations that transform a low-fitness genotype into a genotype that is well-adapted to its environment.

Longitudinal study

A study in which repeated measurements are taken from the same subjects at different time points.

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MacLean, R., Hall, A., Perron, G. et al. The population genetics of antibiotic resistance: integrating molecular mechanisms and treatment contexts. Nat Rev Genet 11, 405–414 (2010). https://doi.org/10.1038/nrg2778

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