Affiliation:
1. Department of Microbial and Molecular Systems, Centre of Microbial and Plant Genetics (CMPG), KU Leuven , Leuven , Belgium
2. Department of Information Technology and the Department of Plant Biotechnology, Biochemistry and Bioinformatics, Ghent University , Ghent , Belgium
Abstract
Abstract
Antibiotic cycling has been proposed as a promising approach to slow down resistance evolution against currently employed antibiotics. It remains unclear, however, to which extent the decreased resistance evolution is the result of collateral sensitivity, an evolutionary trade-off where resistance to one antibiotic enhances the sensitivity to the second, or due to additional effects of the evolved genetic background, in which mutations accumulated during treatment with a first antibiotic alter the emergence and spread of resistance against a second antibiotic via other mechanisms. Also, the influence of antibiotic exposure patterns on the outcome of drug cycling is unknown. Here, we systematically assessed the effects of the evolved genetic background by focusing on the first switch between two antibiotics against Salmonella Typhimurium, with cefotaxime fixed as the first and a broad variety of other drugs as the second antibiotic. By normalizing the antibiotic concentrations to eliminate the effects of collateral sensitivity, we demonstrated a clear contribution of the evolved genetic background beyond collateral sensitivity, which either enhanced or reduced the adaptive potential depending on the specific drug combination. We further demonstrated that the gradient strength with which cefotaxime was applied affected both cefotaxime resistance evolution and adaptation to second antibiotics, an effect that was associated with higher levels of clonal interference and reduced cost of resistance in populations evolved under weaker cefotaxime gradients. Overall, our work highlights that drug cycling can affect resistance evolution independently of collateral sensitivity, in a manner that is contingent on the antibiotic exposure pattern.
Funder
Fonds Wetenschappelijk Onderzoek - Vlaanderen
KU Leuven Research Council
Bijzonder Onderzoeksfonds Ugent
Agentschap voor Innovatie door Wetenschap en Technologie
Publisher
Oxford University Press (OUP)
Subject
Genetics,Molecular Biology,Ecology, Evolution, Behavior and Systematics
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