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

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

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Title: A synthetic lethal approach for compound and target identification in Staphylococcus aureus
Author: Pasquina, Lincoln; Maria, John P. Santa; Wood, B. McKay; Moussa, Samir H.; Matano, Leigh; Santiago, Marina; Martin, Sara E. S.; Lee, Wonsik; Meredith, Timothy C.; Walker, Suzanne

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Citation: Pasquina, Lincoln, John P. Santa Maria, B. McKay Wood, Samir H. Moussa, Leigh Matano, Marina Santiago, Sara E. S. Martin, Wonsik Lee, Timothy C. Meredith, and Suzanne Walker. 2015. “A synthetic lethal approach for compound and target identification in Staphylococcus aureus.” Nature chemical biology 12 (1): 40-45. doi:10.1038/nchembio.1967. http://dx.doi.org/10.1038/nchembio.1967.
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Abstract: The majority of bacterial proteins are dispensable for growth in the laboratory, but nevertheless play 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, which 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 important bacterial processes that can be adapted to numerous organisms.
Published Version: doi:10.1038/nchembio.1967
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684722/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:27320367
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