Structure-activity studies of the inhibition of FabI, the enoyl reductase from Escherichia coli, by triclosan: kinetic analysis of mutant FabIs

Biochemistry
Sharada SivaramanPeter J Tonge

Abstract

Triclosan, a common antibacterial additive used in consumer products, is an inhibitor of FabI, the enoyl reductase enzyme from type II bacterial fatty acid biosynthesis. In agreement with previous studies [Ward, W. H., Holdgate, G. A., Rowsell, S., McLean, E. G., Pauptit, R. A., Clayton, E., Nichols, W. W., Colls, J. G., Minshull, C. A., Jude, D. A., Mistry, A., Timms, D., Camble, R., Hales, N. J., Britton, C. J., and Taylor, I. W. (1999) Biochemistry 38, 12514-12525], we report here that triclosan is a slow, reversible, tight binding inhibitor of the FabI from Escherichia coli. Triclosan binds preferentially to the E.NAD(+) form of the wild-type enzyme with a K(1) value of 23 pM. In agreement with genetic selection experiments [McMurry, L. M., Oethinger, M., and Levy, S. B. (1998) Nature 394, 531-532], the affinity of triclosan for the FabI mutants G93V, M159T, and F203L is substantially reduced, binding preferentially to the E.NAD(+) forms of G93V, M159T, and F203L with K(1) values of 0.2 microM, 4 nM, and 0.9 nM, respectively. Triclosan binding to the E.NADH form of F203L can also be detected and is defined by a K(2) value of 51 nM. We have also characterized the Y156F and A197M mutants to compare and contrast the binding of...Continue Reading

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Citations

Jan 16, 2008·Accounts of Chemical Research·Hao Lu, Peter J Tonge
Aug 12, 2010·Journal of Medicinal Chemistry·Suresh K TipparajuRima L McLeod
Oct 11, 2005·The Journal of Biological Chemistry·Loretha Carlisle-MoorePeter J Tonge
Apr 5, 2008·The Journal of Antimicrobial Chemotherapy·Mark A WebberLaura J V Piddock
Apr 5, 2008·The Journal of Antimicrobial Chemotherapy·Mark A WebberLaura J V Piddock
Mar 14, 2009·The Journal of Antimicrobial Chemotherapy·Chang Ji ZhengWon-Gon Kim
Mar 12, 2011·The Journal of Antimicrobial Chemotherapy·Nina LiuPeter J Tonge
Jun 2, 2011·Antimicrobial Agents and Chemotherapy·Catherine VilchèzeWilliam R Jacobs
Dec 3, 2009·Biological & Pharmaceutical Bulletin·Yun-Ju KwonWon-Gon Kim
Oct 22, 2013·Microbial Drug Resistance : MDR : Mechanisms, Epidemiology, and Disease·Mary LenahanCatherine M Burgess
Dec 8, 2006·Dermatitis : Contact, Atopic, Occupational, Drug·Lauren Campbell, Matthew J Zirwas
Jan 24, 2013·International Journal of Food Microbiology·Elena Ortega MorenteAntonio Gálvez
Apr 22, 2008·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Anastasia KariotiDeniz Tasdemir
Sep 11, 2007·Biochemical and Biophysical Research Communications·Chang Ji ZhengWon-Gon Kim
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May 2, 2006·The Journal of Biological Chemistry·Yong-Mei ZhangCharles O Rock

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