ArticleNature communications2014
Opposing effects of target overexpression reveal drug mechanisms.
Article in Nature communications, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers.
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Who cites it
90 citing papers in PubMed.
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- Regulation of immune-mediated chemoresistance in cancer by lncRNAs: an in-depth review of signaling pathways.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Molecular docking and biological evaluation of a novel IWS1 inhibitor for the treatment of human retroperitoneal liposarcoma.Scientific reports · 2025Article
- Dual Mutations inInternational journal of molecular sciences · 2025Article
- GrcC1 mediates low-level resistance to multiple drugs inMicrobiology spectrum · 2025Article
- Distinguishing mutants that resist drugs via different mechanisms by examining fitness tradeoffs.eLife · 2024Article
- Integrating bacterial molecular genetics with chemical biology for renewed antibacterial drug discovery.The Biochemical journal · 2024Review
- Investigating Antiprotozoal Chemotherapies with Novel Proteomic Tools-Chances and Limitations: A Critical Review.International journal of molecular sciences · 2024Review
- Distinguishing mutants that resist drugs via different mechanisms by examining fitness tradeoffs.bioRxiv : the preprint server for biology · 2024Article
30 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
2 authors.
Funding
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.
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Registered trials
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