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Keohane CE , Steele AD , Fetzer C , Khowsathit J , Van Tyne D , Moynie L , Gilmore MS , Karanicolas J , Sieber SA , Wuest WM
Promysalin Elicits Species-Selective Inhibition of Pseudomonas aeruginosa by Targeting Succinate Dehydrogenase
J Am Chem Soc. 2018 Feb 7;140(5) :1774-1782
PMID: 29300464    PMCID: PMC5869686    URL: https://www.ncbi.nlm.nih.gov/pubmed/29300464
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Natural products have served as an inspiration to scientists both for their complex three-dimensional architecture and exquisite biological activity. Promysalin is one such Pseudomonad secondary metabolite that exhibits narrow-spectrum antibacterial activity, originally isolated from the rhizosphere. We herein utilize affinity-based protein profiling (AfBPP) to identify succinate dehydrogenase (Sdh) as the biological target of the natural product. The target was further validated in silico, in vitro, in vivo, and through the selection, and sequencing, of a resistant mutant. Succinate dehydrogenase plays an essential role in primary metabolism of Pseudomonas aeruginosa as the only enzyme that is involved both in the tricarboxylic acid cycle (TCA) and in respiration via the electron transport chain. These findings add credence to other studies that suggest that the TCA cycle is an understudied target in the development of novel therapeutics to combat P. aeruginosa, a significant pathogen in clinical settings.
1520-5126 Keohane, Colleen E Steele, Andrew D Fetzer, Christian ORCID: http://orcid.org/0000-0001-5510-1544 Khowsathit, Jittasak Van Tyne, Daria Moynie, Lucile Gilmore, Michael S Karanicolas, John ORCID: http://orcid.org/0000-0003-0300-726X Sieber, Stephan A ORCID: http://orcid.org/0000-0002-9400-906X Wuest, William M ORCID: http://orcid.org/0000-0002-5198-7744 R35 GM119426/GM/NIGMS NIH HHS/United States Journal Article United States J Am Chem Soc. 2018 Jan 24. doi: 10.1021/jacs.7b11212.