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Antimicrob. Agents Chemother. doi:10.1128/AAC.01458-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Inhibition of Isolated Mycobacterium tuberculosis Fatty Acid Synthase I by Pyrazinamide Analogs

Department of Chemistry, University at Albany, SUNY, Albany, NY; Infectious Diseases Division, Kaplan Medical Center, affiliated to The Hebrew University, Israel; Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, NY

^* To whom correspondence should be addressed. Email: jwelch{at}uamail.albany.edu.

	Abstract

An analog of pyrazinamide (PZA), 5-chloropyrazinamide (5-Cl-PZA), has previously been shown to inhibit mycobacterial fatty acid synthase I (FASI). FASI has been purified from a recombinant strain of M. smegmatis (M. smegmatis -fas1 attB::M. tuberculosis fas1). Following purification, FASI activity and inhibition was assessed spectrophotometrically by monitoring NADPH oxidation. The observed inhibition was both concentration and structure dependent, being affected by both substitution at the 5-position of the pyrazine nucleus and the nature of ester or N-alkyl group. Under the conditions studied, both 5-Cl-PZA and PZA exhibited concentration and substrate dependence consistent with competitive inhibition of FASI with Ki of 55-59 µM and 2567-2627 µM respectively. The results were validated utilizing a radiolabeled fatty acid synthesis assay. Using this assay, FASI was inhibited by PZA and pyrazinoic acid as well as by a series of PZA analogs.