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

Colleen E. Keohane, Andrew D. Steele, Christian Fetzer, Jittasak Khowsathit, Daria Van Tyne, Lucile Moynié, Michael S. Gilmore, John Karanicolas, Stephan A. Sieber, William M. Wuest*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1774-1782
Number of pages9
JournalJournal of the American Chemical Society
Volume140
Issue number5
DOIs
Publication statusPublished - 7 Feb 2018
Externally publishedYes

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