Activity of n-propyl pyrazinoate against pyrazinamide-resistant Mycobacterium tuberculosis: investigations into mechanism of action of and mechanism of resistance to pyrazinamide.
The mechanism of action of pyrazinamide (PZA) is not known. One hypothesis is that PZA functions as a prodrug of pyrazinoic acid. Susceptibility to PZA correlates with amidase activity of the Mycobacterium tuberculosis isolate in question. PZA-resistant isolates retain susceptibility in vitro to pyrazinoic acid and n-propyl pyrazinoate. Esters of pyrazinoic acid appear to circumvent the requirement for activation by mycobacterial amidase. The MICs of n-propyl pyrazinoate for M. tuberculosis isolates are lower than those of pyrazinoic acid. Further studies to assess the effects of modifications of the alcohol and pyrazine moieties of pyrazinoate esters on in vitro and in vivo antituberculosis activity are under way. This may lead to a candidate compound with enhanced activity against both PZA-susceptible and PZA-resistant M. tuberculosis isolates suitable for clinical development.
Speirs
R J
RJ
Veterans Affairs Medical Center, Syracuse, New York 13210, USA.
Welch
J T
JT
Cynamon
M H
MH
D000581:Amidohydrolases / Q000378:metabolism; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D004352:Drug Resistance, Microbial; D004950:Esterases / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009161:Mycobacterium / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009525:Niacin / Q000096:biosynthesis; D011718:Pyrazinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000904:Antibiotics, Antitubercular; D009525:Niacin; D011718:Pyrazinamide; C005296:pyrazinoic acid; C095794:propyl pyrazinoate; D004950:Esterases; D000581:Amidohydrolases; C022490:pyrazinamide deamidase