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dc.contributor.authorWood, Kevin B
dc.contributor.authorCluzel, Philippe
dc.date.accessioned2014-02-26T13:09:22Z
dc.date.issued2012
dc.identifier.citationWood, Kevin B, and Philippe Cluzel. 2012. Trade-offs between drug toxicity and benefit in the multi-antibiotic resistance system underlie optimal growth of e. coli. BMC Systems Biology 6: 48.en_US
dc.identifier.issn1752-0509en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11801638
dc.description.abstractBackground: Efflux is a widespread mechanism of reversible drug resistance in bacteria that can be triggered by environmental stressors, including many classes of drugs. While such chemicals when used alone are typically toxic to the cell, they can also induce the efflux of a broad range of agents and may therefore prove beneficial to cells in the presence of multiple stressors. The cellular response to a combination of such chemical stressors may be governed by a trade-off between the fitness costs due to drug toxicity and benefits mediated by inducible systems. Unfortunately, disentangling the cost-benefit interplay using measurements of bacterial growth in response to the competing effects of the drugs is not possible without the support of a theoretical framework. Results: Here, we use the well-studied multiple antibiotic resistance (MAR) system in E. coli to experimentally characterize the trade-off between drug toxicity (“cost”) and drug-induced resistance (“benefit”) mediated by efflux pumps. Specifically, we show that the combined effects of a MAR-inducing drug and an antibiotic are governed by a superposition of cost and benefit functions that govern these trade-offs. We find that this superposition holds for all drug concentrations, and it therefore allows us to describe the full dose–response diagram for a drug pair using simpler cost and benefit functions. Moreover, this framework predicts the existence of optimal growth at a non-trivial concentration of inducer. We demonstrate that optimal growth does not coincide with maximum induction of the mar promoter, but instead results from the interplay between drug toxicity and mar induction. Finally, we derived and experimentally validated a general phase diagram highlighting the role of these opposing effects in shaping the interaction between two drugs. Conclusions: Our analysis provides a quantitative description of the MAR system and highlights the trade-off between inducible resistance and the toxicity of the inducing agent in a multi-component environment. The results provide a predictive framework for the combined effects of drug toxicity and induction of the MAR system that are usually masked by bulk measurements of bacterial growth. The framework may also be useful for identifying optimal growth conditions in more general systems where combinations of environmental cues contribute to both transient resistance and toxicity.en_US
dc.description.sponsorshipEngineering and Applied Sciencesen_US
dc.description.sponsorshipMolecular and Cellular Biologyen_US
dc.language.isoen_USen_US
dc.publisherBioMed Centralen_US
dc.relation.isversionofdoi:10.1186/1752-0509-6-48en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3462682/pdf/en_US
dash.licenseLAA
dc.titleTrade-offs between drug toxicity and benefit in the multi-antibiotic resistance system underlie optimal growth of E. colien_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalBMC Systems Biologyen_US
dash.depositing.authorCluzel, Philippe
dc.date.available2014-02-26T13:09:22Z
dc.identifier.doi10.1186/1752-0509-6-48*
dash.contributor.affiliatedCluzel, Philippe


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