Promysalin Elicits Species-Selective Inhibition of Pseudomonas aeruginosa by Targeting Succinate Dehydrogenase

• Type of Material: Article
• Authors: Colleen E. Keohane, Emory University; Andrew D. Steele, Emory University; Christian Fetzer, Technical University of Munich; Jittasak Khowsathit, Fox Chase Cancer Center; Daria Van Tyne, Harvard Medical School; Lucile Maynie, University of Oxford; Michael S. Gilmore, Harvard Medical School; John Karanicolas, Fox Chase Cancer Center; Stephan A. Sieber, Technical University of Munich; William Wuest, Emory University
• Language: English
• Date: 2018-02-07
• Publisher: American Chemical Society
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 American Chemical Society.
• Final Published Version (URL): http://dx.doi.org/10.1021/jacs.7b11212
• Title of Journal or Parent Work: Journal of the American Chemical Society
• ISSN: 0002-7863
• Volume: 140
• Issue: 5
• Start Page: 1774
• End Page: 1782
• Grant/Funding Information: This work was supported by the National Science Foundation CHE1755698(W.M.W.), the National Institute of General Medical Studies R35 GM119426 (W.M.W.), and Temple University. D.V.T. is supported by Grant EY028222 from the National Eye Institute.; Computational resources were provided through National Science Foundation XSEDE allocation MCB130049.
• Keywords: RHIZOSPHERE; Chemistry; Chemistry, Multidisciplinary; Science & Technology; PROTEOME; SUSCEPTIBILITY; ROOTS; RESISTANCE; ACID CYCLE; GENERATION; Physical Sciences
• Research Categories: Chemistry, Physical

Abstract

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.