The mechanism of action of PA-824: Novel insights from transcriptional profiling.

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Manjunatha U, Boshoff HI, Barry CE

The mechanism of action of PA-824: Novel insights from transcriptional profiling.

Commun Integr Biol. 2009 May;2(3):215-8. doi: 10.4161/cib.2.3.7926.

PubMed ID

19641733 [ View in PubMed

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Abstract

The bicyclic nitroimidazole PA-824 is a pro-drug with a very complex mechanism of action active against both replicating and hypoxic, non-replicating Mycobacterium tuberculosis. Microarray analysis of the mode of action of PA-824 showed a puzzling mixed effect both on genes responsive to both cell wall inhibition (like isoniazid) and respiratory poisoning (like cyanide). The aerobic killing mechanism of this drug appears to involve inhibition of cell wall mycolic acid biosynthesis through an as yet unknown molecular mechanism. However, the structure-activity relationships governing aerobic activity do not parallel the relationships determining anaerobic activity. Based on the metabolite profiling of PA-824 and various derivatives by Ddn-mediated activation, we have shown that PA-824 acts directly as an NO donor.1 This respiratory poisoning through nitric oxide release seemed to be a crucial element of anaerobic activity by PA-824. The effect of PA-824 on the respiratory complex under hypoxic non-replicating conditions was also manifested in a rapid drop in intracellular ATP levels, again similar to that observed by cyanide treatment. Thus, transcriptional profiling provided valuable clues to elucidating the molecular mechanism of mycobacterial killing.

DrugBank Data that Cites this Article

Drugs

Pretomanid

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Pretomanid	Cyd operon, Mycobacterium tuberculosis (Protein Group)	Protein group	Mycobacterium tuberculosis	Unknown	Other/unknown	Details
Pretomanid	Enoyl-[acyl-carrier-protein] reductase [NADH]	Protein	Mycobacterium tuberculosis	Unknown	Other/unknown	Details
Pretomanid	Fatty acid synthetase	Protein	Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)	Unknown	Other/unknown	Details
Pretomanid	Nucleoid-associated protein Lsr2	Protein	Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)	Unknown	Other/unknown	Details
Pretomanid	Uncharacterized MFS-type transporter EfpA	Protein	Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)	Unknown	Other/unknown	Details

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Pretomanid	Deazaflavin-dependent nitroreductase	Protein	Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)	Unknown	Substrate	Details