Mechanisms of antibiotic action shape the fitness landscapes of resistance mutations
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2022-08-23
Date Acceptance
2022-08-12
Citation
Computational and Structural Biotechnology Journal, 2022, 20, pp.4688-4703
ISSN
2001-0370
Publisher
Elsevier
Start Page
4688
End Page
4703
Journal / Book Title
Computational and Structural Biotechnology Journal
Volume
20
Copyright Statement
2022 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
License URL
Identifier
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000862294800013&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
Subjects
Antibiotic resistance
BACTERICIDAL ANTIBIOTICS
Biochemistry & Molecular Biology
Biotechnology & Applied Microbiology
Clinical microbiology
COMPENSATORY MUTATIONS
COSTS
EMERGENCE
EVOLUTION
Fitness landscape
FLUOROQUINOLONE RESISTANCE
Global health
GYRASE
Life Sciences & Biomedicine
Multiscale modeling
MUTANT SELECTION WINDOW
PENICILLIN-BINDING PROTEINS
Pharmacodynamics
POPULATION
Science & Technology
Publication Status
Published
Coverage Spatial
Netherlands
Date Publish Online
2022-08-23