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

Abstract

Tuberculosis treatment is shortened to six months by the indispensable addition of pyrazinamide (PZA) to the drug regimen that includes isoniazid and rifampin1,2. 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 Mycobacterium tuberculosis, the PZA analog 5-chloro-pyrazinamide (5-Cl-PZA) displays a broader range of anti-mycobacterial activity4. We have found that the eukaryotic-like fas1 gene5 (encoding fatty acid synthetase I, FASI) from M. avium, M. bovis BCG or M. tuberculosis confers resistance to 5-Cl-PZA when present on multi-copy vectors in M. smegmatis. 5-Cl-PZA and PZA markedly inhibited the activity of M. tuberculosis FASI, the biosynthesis of C16 to C24/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.

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Figure 1: 5-Cl-PZA and PZA inhibit Fasi in mycobacteria.
Figure 2: PZA inhibits M. tuberculosis FASI in mycobacteria.

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Acknowledgements

We thank: A. Kiener of the Biotec division of Lonza for providing 5-hydroxy-pyrazinoic acid, Carlos Vaamonde for M. avium cosmid library, John Chan for critical review of the manuscript, T. Weisbord and R. Lucos for sequence analysis, Ms. J. Nguyen and N. Nakata for help in isolation and processing 5-Cl-PZA resistant mutants. O.Z is a fellow on the Molecular Pathogenesis of Infectious Diseases training grant from the National Institutes of Health.

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Correspondence to William R. Jacobs Jr..

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Zimhony, O., Cox, J., Welch, J. et al. Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis. Nat Med 6, 1043–1047 (2000). https://doi.org/10.1038/79558

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