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JAC Advance Access originally published online on October 16, 2003
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Journal of Antimicrobial Chemotherapy (2003) 52, 790-795
© 2003 The British Society for Antimicrobial Chemotherapy

Mode of action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid

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

Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA

Received 18 June 2003; returned 5 August 2003; revised 14 August 2003; accepted 17 August 2003

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

* Corresponding author. Tel: +1-410-614-2975; Fax: +1-410-955-0105; E-mail: yzhang{at}jhsph.edu

§ Present address. U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21702, USA.


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