Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis

Oren Zimhony, Jeffery S. Cox, John T. Welch, Catherine Vilchèze, William R. Jacobs

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Abstract

Tuberculosis treatment is shortened to six months by the indispensable addition of pyrazinamide (PZA) to the drug regimen that includes isoniazid and rifampin. PZA is a pro-drug of pyrazinoic acid (POA) (ref. 3), whose target of action has never been identified. Although PZA is active only against Mycobocterium tuberculosis, the PZA analog 5-chloro-pyrazinamide (5-CI-PZA) displays a broader range of anti-mycobacterial activity. We have found that the eukaryotic-like fas 1 gene (encoding fatty acid synthetase I, FASI) from M. avium, M. bovis BCG or M. tuberculosis confers resistance to 5-CI-PZA when present on multi-copy vectors in M. smegmatis. 5-CI-PZA and PZA markedly inhibited the activity of M. tuberculosis FASI, the biosynthesis of C16 to C(24/C26) fatty acids from acetyl-CoA (ref.6). Importantly, PZA inhibited FASI in M. tuberculosis in correlation with PZA susceptibility. These results indicate that FASI is a primary target of action for PZA in M. tuberculosis. Further characterization of FASI as a drug target for PZA may allow the development of new drugs to shorten the therapy against M. tuberculosis and may provide more options for treatment against M. bovis, M. avium and drug resistant M. tuberculosis.

Original languageEnglish (US)
Pages (from-to)1043-1047
Number of pages5
JournalNature Medicine
Volume6
Issue number9
DOIs
Publication statusPublished - Sep 1 2000

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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