Pretomanid

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Pretomanid
Pretomanid.svg
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
ChemSpider
KEGG
ChEMBL
Chemical and physical data
Formula C14H12F3N3O5
Molar mass 359.26 g·mol−1
3D model (JSmol)

Pretomanid[1] (PA-824) is an experimental anti-tuberculosis drug.[2][3] Pretomanid is a bicyclic nitroimidazole-like molecule (a nitroimidazopyran) with a very complex mechanism of action. It is active against both replicating and hypoxic, non-replicating Mycobacterium tuberculosis. Microarray analysis of the mode of action of pretomanid showed a puzzling mixed effect both on genes responsive to 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.The respiratory poisoning through nitric oxide release seemed to be a crucial element of anaerobic activity by pretomanid. The effect of pretomanid 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.[4] Recently, a new study showed the influence of the accumulation of methylglyoxal, a toxic metabolite, as an additional killing mechanism of pretomanid in mycobacteria.[5]

Pretomanid recently was shown to be safe, well tolerated, and efficacious at doses of 100–200 mg daily in a dose-ranging study among drug-sensitive, sputum smear–positive, adult pulmonary TB patients [6]

PA-824 was developed at Pathogenesis Corporation and later transferred to the TB Alliance, where it is currently undergoing Phase III clinical trials. [7]

See also[edit]

References[edit]

  1. ^ "PA-824 has a New Generic Name: Pretomanid". Retrieved 12 March 2015. 
  2. ^ Ginsberg AM, Laurenzi MW, Rouse DJ, Whitney KD, Spigelman MK (September 2009). "Safety, tolerability, and pharmacokinetics of PA-824 in healthy subjects". Antimicrob. Agents Chemother. 53 (9): 3720–5. doi:10.1128/AAC.00106-09. PMC 2737845Freely accessible. PMID 19528280. 
  3. ^ Stover CK, Warrener P, VanDevanter DR, et al. (2000). "A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis". Nature. 405 (6789): 962–6. doi:10.1038/35016103. PMID 10879539. 
  4. ^ Manjunatha U; Boshoff IM Helena; Barry CE (May–Jun 2009). "The mechanism of action of PA-824". Commun Integr Biol. 2 (3): 215–218. PMC 2717523Freely accessible. PMID 19641733. 
  5. ^ Baptista, Rafael; Fazakerley, David M.; Beckmann, Manfred; Baillie, Les; Mur, Luis A. J. (2018-03-23). "Untargeted metabolomics reveals a new mode of action of pretomanid (PA-824)". Scientific Reports. 8 (1). doi:10.1038/s41598-018-23110-1. ISSN 2045-2322. 
  6. ^ "PA-824 | Pipeline Report". Retrieved 12 March 2015. 
  7. ^ "Pretomanid". TB Alliance. Retrieved February 17, 2017.