@article{0163f05e534b46dc92801547a917fe15,
title = "Promysalin Elicits Species-Selective Inhibition of Pseudomonas aeruginosa by Targeting Succinate Dehydrogenase",
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.",
author = "Keohane, {Colleen E.} and Steele, {Andrew D.} and Christian Fetzer and Jittasak Khowsathit and {Van Tyne}, Daria and Lucile Moyni{\'e} and Gilmore, {Michael S.} and John Karanicolas and Sieber, {Stephan A.} and Wuest, {William M.}",
note = "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. We thank Prof. Eric Brown (McMaster University), Prof. James Naismith (The University of St. Andrews), Prof. Louise Charkoudian (Haverford College), and Mr. Sean Rossiter (Temple University) for fruitful discussions, Materia, Inc. for olefin metathesis catalysts, Dr. Charles W. Funding Information: Ross III, Director - Automated Synthesis and Characterization, of the University of Pennsylvania Chemistry Department Mass Spectrometry Facilities for mass spectral data, Dr. Charles DeBrosse for assistance with spectroscopy, and Profs. De Mot (KU-Leuven) and O{\textquoteright}Toole (Dartmouth Medical School) for strains. We are grateful to OpenEye Scientific Software (Santa Fe, NM) for providing an academic license for the use of OMEGA, ROCS, and FastROCS. Computational resources were provided through National Science Foundation XSEDE allocation MCB130049. Publisher Copyright: {\textcopyright} 2018 American Chemical Society.",
year = "2018",
month = feb,
day = "7",
doi = "10.1021/jacs.7b11212",
language = "English",
volume = "140",
pages = "1774--1782",
journal = "Journal of the American Chemical Society",
issn = "0002-7863",
publisher = "American Chemical Society",
number = "5",
}