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Antimicrobial Agents and Chemotherapy, July 2007, p. 2430-2435, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01458-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Silvana C. Ngo,1 Oren Zimhony,2 Woo Jin Chung,1 Halimah Sayahi,1 William R. Jacobs Jr.,3 and John T. Welch1*

Department of Chemistry, University at Albany, SUNY, Albany, New York,1 Infectious Diseases Division, Kaplan Medical Center, The Hebrew University, Jerusalem, Rehovot, Israel,2 Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York3

Received 20 November 2006/ Returned for modification 10 April 2007/ Accepted 30 April 2007

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 {Delta}fas1 attB::M. tuberculosis fas1). Following purification, FASI activity and inhibition were 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 the 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 Kis of 55 to 59 µM and 2,567 to 2,627 µM, respectively. The results were validated utilizing a radiolabeled fatty acid synthesis assay. This assay showed that FASI was inhibited by PZA and pyrazinoic acid as well as by a series of PZA analogs.

* Corresponding author. Mailing address: Department of Chemistry, University at Albany-SUNY, Albany, NY 12222. Phone: (518) 442-4455. Fax: (518) 442-3462. E-mail: jwelch{at}uamail.albany.edu

{triangledown} Published ahead of print on 7 May 2007.

Antimicrobial Agents and Chemotherapy, July 2007, p. 2430-2435, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01458-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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