Rapid Inhibitor Discovery by Exploiting Synthetic Lethality

Jacob D. Muscato, Heidi G. Morris, Aaron Mychack, Mithila Rajagopal, Vadim Baidin, Anthony R. Hesser, Wonsik Lee, Kemal İnecik, Laura J. Wilson, Christina M. Kraml, Timothy C. Meredith, Suzanne Walker

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Synthetic lethality occurs when inactivation of two genes is lethal but inactivation of either single gene is not. This phenomenon provides an opportunity for efficient compound discovery. Using differential growth screens, one can identify biologically active compounds that selectively inhibit proteins within the synthetic lethal network of any inactivated gene. Here, based purely on synthetic lethalities, we identified two compounds as the only possible inhibitors of Staphylococcus aureus lipoteichoic acid (LTA) biosynthesis from a screen of ∼230,000 compounds. Both compounds proved to inhibit the glycosyltransferase UgtP, which assembles the LTA glycolipid anchor. UgtP is required for β-lactam resistance in methicillin-resistant S. aureus (MRSA), and the inhibitors restored sensitivity to oxacillin in a highly resistant S. aureus strain. As no other compounds were pursued as possible LTA glycolipid assembly inhibitors, this work demonstrates the extraordinary efficiency of screens that exploit synthetic lethality to discover compounds that target specified pathways. The general approach should be applicable not only to other bacteria but also to eukaryotic cells.

Original languageEnglish (US)
Pages (from-to)3696-3705
Number of pages10
JournalJournal of the American Chemical Society
Issue number8
StatePublished - Mar 2 2022

All Science Journal Classification (ASJC) codes

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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