Pyrazinoic Acid and Its n-Propyl Ester Inhibit Fatty Acid Synthase

The activity of different analogs of pyrazinamide on Mycobacterium tuberculosis fatty acid synthase type I (FASI) in replicating bacilli was studied. Palmitic acid biosynthesis was diminished by 96 % in bacilli treated with n-propyl pyrazinoate, 94 % in bacilli treated with 5-chloro-pyrazinamide, and 97 % in bacilli treated with pyrazinoic acid, the pharmacologically active agent of pyrazinamide. We conclude that the minimal structure of pyrazine ring with an acyl group is sufficient for FASI inhibition and antimycobacterial activity. Pyrazinamide (PZA), a first-line sterilizing drug in tubercu-losis chemotherapy (2, 6), is the prodrug of the pharmacolog-ically active agent pyrazinoic acid (POA). POA is released by amide hydrolysis of PZA (Fig. 1) (7, 11). Mycobacterium tuber-culosis is the only mycobacterial species that is susceptible to both PZA and POA, while Mycobacterium bovis is susceptible only to POA (5, 12, 14). Interestingly, the antimycobacterial activity of these compounds takes place only in an acidic me-dium (9, 14), which allows for the intracellular accumulation of POA. In addition, M. tuberculosis is uniquely susceptible t