Uses
A novel anti-tuberculosis drug.
Biological Activity
pa-824, a bicyclic nitroimidazoles, is an anti-tuberculosis (tb) agent that exerts potent in vitro activity against mycobacterium tuberculosis with the minimal inhibition concentration (mic) ranging from 0.015 μg/ml to 0.25 μg/ml and remains actively against a wide range of isolates that are resistant to commonly used anti-tb agents leading to its successful application in the treatment of tb [1].pa-824 has been found to exhibit bactericidal activity against replicating bacilli and non-replicating bacilli under hypoxic or prolonged culture conditions in a dose dependent fashion through two possible mechanisms, which include pa-824 induced inhibition of ketomycolate synthesis and pa-824 mediated donation of nitric oxide during enzymatic nitro-reduction [1].
Biochem/physiol Actions
PA-824 is an anti-tuberculosis drug.
Enzyme inhibitor
This first-in-class tuberculosis pro-drug (FW = 359.26 g/mol; CAS 187235-
37-6), also named (6S) -2-nitro-6-{[4- (trifluoromethoxy) -benzyl]oxy}-6,7-
dihydro-5H-imidazo[2,1-b][1,3]oxazine, is active against both replicating
and hypoxic, non-replicating forms of Mycobacterium tuberculosis. After
activation by a process that depends on M. tuberculosis F420 cofactor, PA-
824 exerts its bacteriocidal action by inhibiting protein biosynthesis and cell
wall lipid synthesis. Its reduction potential does not appear to be the
main driver for inhibitor efficacy. Significantly, PA-824 generates a des-
nitro metabolite, along with a reactive nitrogen species (including nitric
oxide), that may be effectors of the anaerobic activity of these compounds
. Furthermore, nitric oxide scavengers protected M. tuberculosis from the
lethal effects of the drug. This finding suggests PA-824 releases a lethal
nitrogen oxide-like metabolite that factors into its bacteriocidal action. That
PA-824 is without effect on M. leprae is consistent with the absence of a
required activating enzyme, namely nitroimidazo-oxazine-specific
nitroreductase (encoded by Rv3547), in the M. leprae genome.
References
[1] ahmad z, peloquin ca, singh rp, derendorf h, tyagi s, ginsberg a, grosset jh, nuermberger el. pa-824 exhibits time-dependent activity in a murine model of tuberculosis. antimicrob agents chemother. 2011 jan;55(1):239-45. doi: 10.1128/aac.00849-10. epub 2010 oct 11.
