Key Points
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Across the diverse biological systems discussed in this Review, the underlying principles concerning the mechanisms and dynamics of resistance development are similar.
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Drug resistance has emerged in all biological systems in which drugs are used as a standard therapeutic strategy to control infections or cancer. There is an urgent need not only to develop new drugs to support effective therapy but also to develop a better understanding of the underlying mechanisms and forces that drive resistance development.
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Large population sizes and/or high mutation rates ensure that the emergence of drug resistance is not limited by mutation supply in HIV, in many bacterial infections or in human cancers. Mutation supply may be a limiting factor for fungal and parasitic infections.
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Horizontal gene transfer (HGT) from a very broad gene pool substantially contributes to the emergence of drug resistance in bacteria but is absent as a source of genetic variation in the other systems discussed. We currently know very little about the dynamics and trajectories of HGT events and have a very poor ability to make predictions.
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The study and understanding of the dynamics of growth and competition within complex populations subjected to drug therapy are being advanced by the increasing application of next-generation sequencing technologies.
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In biological systems in which resistance emergence has long been acknowledged to be a problem (particularly HIV infection and human cancer), therapy with combinations of drugs is standard of care. The systematic use of drug combinations in the treatment of bacterial, fungal and parasitic infections might be the most effective short-term means to slow resistance emergence.
Abstract
Drug therapy has a crucial role in the treatment of viral, bacterial, fungal and protozoan infections, as well as the control of human cancer. The success of therapy is being threatened by the increasing prevalence of resistance. We examine and compare mechanisms of drug resistance in these diverse biological systems (using HIV and Plasmodium falciparum as examples of viral and protozoan pathogens, respectively) and discuss how factors — such as mutation rates, fitness effects of resistance, epistasis and clonal interference — influence the evolutionary trajectories of drug-resistant clones. We describe commonalities and differences related to resistance development that could guide strategies to improve therapeutic effectiveness and the development of a new generation of drugs.
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Acknowledgements
D.H. and D.I.A. acknowledge funding from the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115583, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in kind contribution. D.H. and D.I.A. also acknowledge support from Vetenskapsrådet (Swedish Science Council), SSF (Swedish Strategic Science Foundation), Vinnova (Swedish Innovation Science), and the Knut and Alice Wallenberg Foundation (RiboCore Project). D.I.A. acknowledges support from the EU (EvoTar project).
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Glossary
- Isogenic variants
-
Genetic variants that are derived from a single cell or genotype.
- Epistatic
-
Refers to the phenomenon of epistasis, which involves interactions (genetic, regulatory, and physiological) between or within genes and results in non-additive effects with regard to phenotype.
- Population bottlenecks
-
The concept that only a limited number of individuals (and thus genotypes) act as founders of the next generation of cells or organisms.
- Fixation
-
When there are at least two variants of a gene in a population, fixation refers to the situation when, owing to selection or chance fluctuations, only one allele remains.
- Deleterious
-
A mutation that reduces relative fitness under a particular condition.
- Sweep
-
A selective sweep is the reduction or elimination of variation within a population as a result of an increase in the proportion of one 'successful' variant.
- Minimal inhibitory concentration
-
(MIC). The lowest concentration of an antimicrobial drug that, under a set of agreed conditions, inhibits the visible growth of a microorganism after overnight incubation.
- Pleiotropic
-
When one gene influences multiple phenotypic traits.
- Resistome
-
The collection of all of the antibiotic resistance genes and their precursors in both pathogenic and non-pathogenic bacteria.
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Hughes, D., Andersson, D. Evolutionary consequences of drug resistance: shared principles across diverse targets and organisms. Nat Rev Genet 16, 459–471 (2015). https://doi.org/10.1038/nrg3922
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DOI: https://doi.org/10.1038/nrg3922
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