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Opposing effects of target overexpression reveal drug mechanisms

Author

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  • Adam C. Palmer

    (Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA)

  • Roy Kishony

    (Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA
    Faculty of Biology, Technion-Israel Institute of Technology)

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.

Suggested Citation

  • Adam C. Palmer & Roy Kishony, 2014. "Opposing effects of target overexpression reveal drug mechanisms," Nature Communications, Nature, vol. 5(1), pages 1-8, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5296
    DOI: 10.1038/ncomms5296
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    Cited by:

    1. Fabrizio Clarelli & Adam Palmer & Bhupender Singh & Merete Storflor & Silje Lauksund & Ted Cohen & Sören Abel & Pia Abel zur Wiesch, 2020. "Drug-target binding quantitatively predicts optimal antibiotic dose levels in quinolones," PLOS Computational Biology, Public Library of Science, vol. 16(8), pages 1-27, August.
    2. Nadine Bongaerts & Zainab Edoo & Ayan A. Abukar & Xiaohu Song & Sebastián Sosa-Carrillo & Sarah Haggenmueller & Juline Savigny & Sophie Gontier & Ariel B. Lindner & Edwin H. Wintermute, 2022. "Low-cost anti-mycobacterial drug discovery using engineered E. coli," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Maxime Mistretta & Mena Cimino & Pascal Campagne & Stevenn Volant & Etienne Kornobis & Olivier Hebert & Christophe Rochais & Patrick Dallemagne & Cédric Lecoutey & Camille Tisnerat & Alban Lepailleur , 2024. "Dynamic microfluidic single-cell screening identifies pheno-tuning compounds to potentiate tuberculosis therapy," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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