Journal Article

Mode of action of pyrazinamide: disruption of <i> Mycobacterium tuberculosis</i> membrane transport and energetics by pyrazinoic acid

Ying Zhang, Mary Margaret Wade, Angelo Scorpio, Hao Zhang and Zhonghe Sun

in Journal of Antimicrobial Chemotherapy

Published on behalf of British Society for Antimicrobial Chemotherapy

Volume 52, issue 5, pages 790-795
Published in print November 2003 | ISSN: 0305-7453
Published online November 2003 | e-ISSN: 1460-2091 | DOI: http://dx.doi.org/10.1093/jac/dkg446
Mode of action of pyrazinamide: disruption of  Mycobacterium tuberculosis membrane transport and energetics  by pyrazinoic acid

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Pyrazinamide is an important sterilizing drug that shortens tuberculosis (TB) therapy. However, the mechanism of action of pyrazinamide is poorly understood because of its unusual properties. Here we show that pyrazinoic acid, the active moiety of pyrazinamide, disrupted membrane energetics and inhibited membrane transport function in Mycobacterium tuberculosis. The preferential activity of pyrazinamide against old non-replicating bacilli correlated with their low membrane potential and the disruption of membrane potential by pyrazinoic acid and acid pH. Inhibitors of membrane energetics increased the antituberculous activity of pyrazinamide. These findings shed new light on the mode of action of pyrazinamide and may help in the design of new drugs that shorten therapy.

Keywords: Keywords: tuberculosis, mechanism of action, membrane potential, M. tuberculosis

Journal Article.  4131 words.  Illustrated.

Subjects: Medical Oncology ; Critical Care

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