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- W2035270506 abstract "Overexpression of a drug’s molecular target often increases drug resistance, offering a pathway for adaptive evolution and a tool for target identification. It is unclear though why this phenomenon applies to some drugs but not others. Here we gradually overexpressed antibiotic targets in Escherichia coli and found that drug resistance can increase, remain unchanged, decrease or even change non-monotonically. Even a single target can produce opposing responses to its different inhibitors. We explain these contradicting effects with quantitative models of enzyme inhibition that account for fitness costs and the biochemical activity or inactivity of drug–enzyme complexes. Thus, target overexpression confers resistance or sensitivity as a predictable property of drug mechanism, explaining its variable presence in nature as a resistance mechanism. Though overexpression screens may fail at identifying unknown targets, overexpressing known or putative targets provides a systematic approach to distinguish between simple inhibition and complex mechanisms of drug action. Overexpression of a drug’s molecular target increases drug resistance in some cases. Here the authors show that overexpressing antibiotic targets in Escherichia colican cause positive and negative changes in drug resistance, depending on whether the drug induces harmful reactions involving its target." @default.
- W2035270506 created "2016-06-24" @default.
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- W2035270506 date "2014-07-01" @default.
- W2035270506 modified "2023-10-01" @default.
- W2035270506 title "Opposing effects of target overexpression reveal drug mechanisms" @default.
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- W2035270506 doi "https://doi.org/10.1038/ncomms5296" @default.
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