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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.<\/jats:p>","DOI":"10.1093\/molbev\/msac257","type":"journal-article","created":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T05:01:04Z","timestamp":1670389264000},"source":"Crossref","is-referenced-by-count":24,"title":["Antibiotic Cycling Affects Resistance Evolution Independently of Collateral Sensitivity"],"prefix":"10.1093","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5530-4269","authenticated-orcid":false,"given":"Pauline","family":"Brepoels","sequence":"first","affiliation":[{"name":"Department of Microbial and Molecular Systems, Centre of Microbial and Plant Genetics (CMPG), KU Leuven , Leuven , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenny","family":"Appermans","sequence":"additional","affiliation":[{"name":"Department of Microbial and Molecular Systems, Centre of Microbial and Plant Genetics (CMPG), KU Leuven , Leuven , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilo Andres","family":"P\u00e9rez-Romero","sequence":"additional","affiliation":[{"name":"Department of Information Technology and the Department of Plant Biotechnology, Biochemistry and Bioinformatics, Ghent University , Ghent , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bram","family":"Lories","sequence":"additional","affiliation":[{"name":"Department of Microbial and Molecular Systems, Centre of Microbial and Plant Genetics (CMPG), KU Leuven , Leuven , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2169-4588","authenticated-orcid":false,"given":"Kathleen","family":"Marchal","sequence":"additional","affiliation":[{"name":"Department of Information Technology and the Department of Plant Biotechnology, Biochemistry and Bioinformatics, Ghent University , Ghent , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5021-2069","authenticated-orcid":false,"given":"Hans P","family":"Steenackers","sequence":"additional","affiliation":[{"name":"Department of Microbial and Molecular Systems, Centre of Microbial and Plant Genetics (CMPG), KU Leuven , Leuven , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,12,8]]},"reference":[{"key":"2022122218430933900_msac257-B1","first-page":"270","article-title":"The European union summary report on antimicrobial resistance in zoonotic and indicator bacteria from humans, animals and food in 2016","volume":"16","author":"EFSA, ECDC","year":"2018","journal-title":"EFSA J"},{"key":"2022122218430933900_msac257-B2","doi-asserted-by":"crossref","first-page":"2428","DOI":"10.1128\/AAC.00084-08","article-title":"Ramr mutations involved in efflux-mediated multidrug resistance in 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