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Antibiotic cycling affects resistance evolution independently of collateral sensitivity

Pauline Brepoels, Kenny Appermans, Camilo Andrés Pérez Romero (UGent) , Bram Lories, Kathleen Marchal (UGent) and Hans P. Steenackers
(2022) MOLECULAR BIOLOGY AND EVOLUTION. 39(12).
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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.
Keywords
MEDIATED MULTIDRUG-RESISTANCE, ESCHERICHIA-COLI, HISTIDINE KINASE, CORE, DOMAIN, BINDING, PATHS, ACRB, ENVZ, PHARMACODYNAMICS, TYPHIMURIUM

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MLA
Brepoels, Pauline, et al. “Antibiotic Cycling Affects Resistance Evolution Independently of Collateral Sensitivity.” MOLECULAR BIOLOGY AND EVOLUTION, vol. 39, no. 12, 2022, doi:10.1093/molbev/msac257.
APA
Brepoels, P., Appermans, K., Pérez Romero, C. A., Lories, B., Marchal, K., & Steenackers, H. P. (2022). Antibiotic cycling affects resistance evolution independently of collateral sensitivity. MOLECULAR BIOLOGY AND EVOLUTION, 39(12). https://doi.org/10.1093/molbev/msac257
Chicago author-date
Brepoels, Pauline, Kenny Appermans, Camilo Andrés Pérez Romero, Bram Lories, Kathleen Marchal, and Hans P. Steenackers. 2022. “Antibiotic Cycling Affects Resistance Evolution Independently of Collateral Sensitivity.” MOLECULAR BIOLOGY AND EVOLUTION 39 (12). https://doi.org/10.1093/molbev/msac257.
Chicago author-date (all authors)
Brepoels, Pauline, Kenny Appermans, Camilo Andrés Pérez Romero, Bram Lories, Kathleen Marchal, and Hans P. Steenackers. 2022. “Antibiotic Cycling Affects Resistance Evolution Independently of Collateral Sensitivity.” MOLECULAR BIOLOGY AND EVOLUTION 39 (12). doi:10.1093/molbev/msac257.
Vancouver
1.
Brepoels P, Appermans K, Pérez Romero CA, Lories B, Marchal K, Steenackers HP. Antibiotic cycling affects resistance evolution independently of collateral sensitivity. MOLECULAR BIOLOGY AND EVOLUTION. 2022;39(12).
IEEE
[1]
P. Brepoels, K. Appermans, C. A. Pérez Romero, B. Lories, K. Marchal, and H. P. Steenackers, “Antibiotic cycling affects resistance evolution independently of collateral sensitivity,” MOLECULAR BIOLOGY AND EVOLUTION, vol. 39, no. 12, 2022.
@article{01GQPTQFN9VR413822QHR2QW30,
  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.}},
  articleno    = {{msac257}},
  author       = {{Brepoels, Pauline and Appermans, Kenny and Pérez Romero, Camilo Andrés and  Lories, Bram and Marchal, Kathleen and  Steenackers, Hans P.}},
  issn         = {{0737-4038}},
  journal      = {{MOLECULAR BIOLOGY AND EVOLUTION}},
  keywords     = {{MEDIATED MULTIDRUG-RESISTANCE,ESCHERICHIA-COLI,HISTIDINE KINASE,CORE,DOMAIN,BINDING,PATHS,ACRB,ENVZ,PHARMACODYNAMICS,TYPHIMURIUM}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{21}},
  title        = {{Antibiotic cycling affects resistance evolution independently of collateral sensitivity}},
  url          = {{http://doi.org/10.1093/molbev/msac257}},
  volume       = {{39}},
  year         = {{2022}},
}
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