On repeatability and directionality of collateral effects of drug resistance evolution
Louage, M.; Trubenova, B.
Show abstract
Evolution of drug resistance to one drug can alter the minimum inhibitory concentration to another drug. This phenomenon, known as a collateral effect, can manifest as either cross-resistance or collateral sensitivity. Various patterns of collateral effects have been observed experimentally. Repeated adaptation from the same parental strain may result in variable collateral effects; this is non-repeatability. Additionally, adaptation of a pathogen to one drug may produce a specific collateral effect to a second drug, while altering the order of drug exposure can result in a different, or even absent, collateral effect. This phenomenon is termed unidirectionality. The genetic and evolutionary mechanisms underlying these patterns remain incompletely characterised. Here, we propose a frame-work that integrates pharmacodynamics and population genetics and provide minimal examples to explain these patterns and their combinations. Furthermore, we demonstrate that drug concentration and selection regime strongly influence patterns of collateral effects, including repeatability, directionality, and their temporal dynamics.
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