A synthetic lethal approach for compound and target identification in Staphylococcus aureus

Lincoln Pasquina, John P. Santa Maria, B. McKay Wood, Samir H. Moussa, Leigh M. Matano, Marina Santiago, Sara E.S. Martin, Wonsik Lee, Timothy C. Meredith, Suzanne Walker

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

The majority of bacterial proteins are dispensable for growth in the laboratory but nevertheless have important physiological roles. There are no systematic approaches to identify cell-permeable small-molecule inhibitors of these proteins. We demonstrate a strategy to identify such inhibitors that exploits synthetic lethal relationships both for small-molecule discovery and for target identification. Applying this strategy in Staphylococcus aureus, we have identified a compound that inhibits DltB, a component of the teichoic acid D-alanylation machinery that has been implicated in virulence. This D-alanylation inhibitor sensitizes S. aureus to aminoglycosides and cationic peptides and is lethal in combination with a wall teichoic acid inhibitor. We conclude that DltB is a druggable target in the D-alanylation pathway. More broadly, the work described demonstrates a systematic method to identify biologically active inhibitors of major bacterial processes that can be adapted to numerous organisms.

Original languageEnglish (US)
Pages (from-to)40-45
Number of pages6
JournalNature Chemical Biology
Volume12
Issue number1
DOIs
StatePublished - Jan 2016

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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