Mode of action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid.
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.
Zhang
Ying
Y
Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA. yzhang@jhsph.edu
Wade
Mary Margaret
MM
Scorpio
Angelo
A
Zhang
Hao
H
Sun
Zhonghe
Z
D000995:Antitubercular Agents / Q000494:pharmacology*; D001386:Azides / Q000494:pharmacology; D004024:Dicyclohexylcarbodiimide / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D012402:Rotenone / Q000494:pharmacology
D000995:Antitubercular Agents; D001386:Azides; D012402:Rotenone; D011718:Pyrazinamide; C005296:pyrazinoic acid; D004024:Dicyclohexylcarbodiimide