Inhibition of isolated Mycobacterium tuberculosis fatty acid synthase I by pyrazinamide analogs

Silvana C. Ngo, Oren Zimhony, Jin Chung Woo, Halimah Sayahi, William R. Jacobs, John T. Welch

Research output: Contribution to journalArticle

59 Scopus citations

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 Δfas1 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.

Original languageEnglish (US)
Pages (from-to)2430-2435
Number of pages6
JournalAntimicrobial agents and chemotherapy
Volume51
Issue number7
DOIs
StatePublished - Jul 2007

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Fingerprint Dive into the research topics of 'Inhibition of isolated Mycobacterium tuberculosis fatty acid synthase I by pyrazinamide analogs'. Together they form a unique fingerprint.

  • Cite this