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

• Published in: Journal of antimicrobial chemotherapy Vol. 52; no. 5; pp. 790 - 795
• Main Authors: Zhang, Ying, Wade, Mary Margaret, Scorpio, Angelo, Zhang, Hao, Sun, Zhonghe
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-11-2003; Oxford Publishing Limited (England)
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antitubercular Agents - pharmacology; Azides - pharmacology; Biological and medical sciences; Dicyclohexylcarbodiimide - pharmacology; Humans; Hydrogen-Ion Concentration; M. tuberculosis; mechanism of action; Medical sciences; membrane potential; Membrane Potentials - drug effects; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - growth & development; Mycobacterium tuberculosis - metabolism; Pharmacology. Drug treatments; Pyrazinamide - analogs & derivatives; Pyrazinamide - pharmacology; Rotenone - pharmacology; tuberculosis; Mycobacterium tuberculosis; Mycobacteriales; Membrane transport; Mycobacteriaceae; Bacteria; Actinomycetes; Antituberculous agent; Membrane potential; Antibacterial agent; Mechanism of action; Pyrazinamide; In vitro
• ISSN: 0305-7453; 1460-2091; 1460-2091
• DOI: 10.1093/jac/dkg446

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.