Cargando…
Mechanisms of antibiotic action shape the fitness landscapes of resistance mutations
Antibiotic-resistant pathogens are a major public health threat. A deeper understanding of how an antibiotic’s mechanism of action influences the emergence of resistance would aid in the design of new drugs and help to preserve the effectiveness of existing ones. To this end, we developed a model th...
Autores principales: | , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Research Network of Computational and Structural Biotechnology
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9463365/ https://www.ncbi.nlm.nih.gov/pubmed/36147681 http://dx.doi.org/10.1016/j.csbj.2022.08.030 |
_version_ | 1784787381270872064 |
---|---|
author | Hemez, Colin Clarelli, Fabrizio Palmer, Adam C. Bleis, Christina Abel, Sören Chindelevitch, Leonid Cohen, Theodore Abel zur Wiesch, Pia |
author_facet | Hemez, Colin Clarelli, Fabrizio Palmer, Adam C. Bleis, Christina Abel, Sören Chindelevitch, Leonid Cohen, Theodore Abel zur Wiesch, Pia |
author_sort | Hemez, Colin |
collection | PubMed |
description | Antibiotic-resistant pathogens are a major public health threat. A deeper understanding of how an antibiotic’s mechanism of action influences the emergence of resistance would aid in the design of new drugs and help to preserve the effectiveness of existing ones. To this end, we developed a model that links bacterial population dynamics with antibiotic-target binding kinetics. Our approach allows us to derive mechanistic insights on drug activity from population-scale experimental data and to quantify the interplay between drug mechanism and resistance selection. We find that both bacteriostatic and bactericidal agents can be equally effective at suppressing the selection of resistant mutants, but that key determinants of resistance selection are the relationships between the number of drug-inactivated targets within a cell and the rates of cellular growth and death. We also show that heterogeneous drug-target binding within a population enables resistant bacteria to evolve fitness-improving secondary mutations even when drug doses remain above the resistant strain’s minimum inhibitory concentration. Our work suggests that antibiotic doses beyond this “secondary mutation selection window” could safeguard against the emergence of high-fitness resistant strains during treatment. |
format | Online Article Text |
id | pubmed-9463365 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Research Network of Computational and Structural Biotechnology |
record_format | MEDLINE/PubMed |
spelling | pubmed-94633652022-09-21 Mechanisms of antibiotic action shape the fitness landscapes of resistance mutations Hemez, Colin Clarelli, Fabrizio Palmer, Adam C. Bleis, Christina Abel, Sören Chindelevitch, Leonid Cohen, Theodore Abel zur Wiesch, Pia Comput Struct Biotechnol J Research Article Antibiotic-resistant pathogens are a major public health threat. A deeper understanding of how an antibiotic’s mechanism of action influences the emergence of resistance would aid in the design of new drugs and help to preserve the effectiveness of existing ones. To this end, we developed a model that links bacterial population dynamics with antibiotic-target binding kinetics. Our approach allows us to derive mechanistic insights on drug activity from population-scale experimental data and to quantify the interplay between drug mechanism and resistance selection. We find that both bacteriostatic and bactericidal agents can be equally effective at suppressing the selection of resistant mutants, but that key determinants of resistance selection are the relationships between the number of drug-inactivated targets within a cell and the rates of cellular growth and death. We also show that heterogeneous drug-target binding within a population enables resistant bacteria to evolve fitness-improving secondary mutations even when drug doses remain above the resistant strain’s minimum inhibitory concentration. Our work suggests that antibiotic doses beyond this “secondary mutation selection window” could safeguard against the emergence of high-fitness resistant strains during treatment. Research Network of Computational and Structural Biotechnology 2022-08-24 /pmc/articles/PMC9463365/ /pubmed/36147681 http://dx.doi.org/10.1016/j.csbj.2022.08.030 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Hemez, Colin Clarelli, Fabrizio Palmer, Adam C. Bleis, Christina Abel, Sören Chindelevitch, Leonid Cohen, Theodore Abel zur Wiesch, Pia Mechanisms of antibiotic action shape the fitness landscapes of resistance mutations |
title | Mechanisms of antibiotic action shape the fitness landscapes of resistance mutations |
title_full | Mechanisms of antibiotic action shape the fitness landscapes of resistance mutations |
title_fullStr | Mechanisms of antibiotic action shape the fitness landscapes of resistance mutations |
title_full_unstemmed | Mechanisms of antibiotic action shape the fitness landscapes of resistance mutations |
title_short | Mechanisms of antibiotic action shape the fitness landscapes of resistance mutations |
title_sort | mechanisms of antibiotic action shape the fitness landscapes of resistance mutations |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9463365/ https://www.ncbi.nlm.nih.gov/pubmed/36147681 http://dx.doi.org/10.1016/j.csbj.2022.08.030 |
work_keys_str_mv | AT hemezcolin mechanismsofantibioticactionshapethefitnesslandscapesofresistancemutations AT clarellifabrizio mechanismsofantibioticactionshapethefitnesslandscapesofresistancemutations AT palmeradamc mechanismsofantibioticactionshapethefitnesslandscapesofresistancemutations AT bleischristina mechanismsofantibioticactionshapethefitnesslandscapesofresistancemutations AT abelsoren mechanismsofantibioticactionshapethefitnesslandscapesofresistancemutations AT chindelevitchleonid mechanismsofantibioticactionshapethefitnesslandscapesofresistancemutations AT cohentheodore mechanismsofantibioticactionshapethefitnesslandscapesofresistancemutations AT abelzurwieschpia mechanismsofantibioticactionshapethefitnesslandscapesofresistancemutations |