PA-824 Kills Nonreplicating Mycobacterium tuberculosis by Intracellular NO Release

Nitroreductase Nitroimidazole
DOI: 10.1126/science.1164571 Publication Date: 2008-11-27T22:36:45Z
ABSTRACT
Bicyclic nitroimidazoles, including PA-824, are exciting candidates for the treatment of tuberculosis. These prodrugs require intracellular activation their biological function. We found that Rv3547 is a deazaflavin-dependent nitroreductase (Ddn) converts PA-824 into three primary metabolites; major one corresponding des-nitroimidazole (des-nitro). When derivatives were used, amount des-nitro metabolite formed was highly correlated with anaerobic killing Mycobacterium tuberculosis (Mtb). Des-nitro formation generated reactive nitrogen species, nitric oxide (NO), which effectors activity these compounds. Furthermore, NO scavengers protected bacilli from lethal effects drug. Thus, compounds may act as donors and could augment mechanism intrinsic to innate immune system.
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