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

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Ngo SC, Zimhony O, Chung WJ, Sayahi H, Jacobs WR Jr, Welch JT

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

Antimicrob Agents Chemother. 2007 Jul;51(7):2430-5. Epub 2007 May 7.

PubMed ID

17485499 [ View in PubMed

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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 Deltafas1 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 K(i)s of 55 to 59 microM and 2,567 to 2,627 microM, 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.

DrugBank Data that Cites this Article

Drugs

Pyrazinamide

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Pyrazinamide	Fatty acid synthetase	Protein	Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)	Yes	Inhibitor	Details