Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/35844
Title: Understanding Cofactor F420 dependent mechanism(s) in the activation of bicycle nitroimidazoles and in the physiology of Mycobacterium tuberculosis
Authors: MEERA GURUMURTHY
Keywords: Mycobacterium, Tuberculosis, F420, PA-824, nitroimidazoles, cofactor
Issue Date: 17-Aug-2012
Source: MEERA GURUMURTHY (2012-08-17). Understanding Cofactor F420 dependent mechanism(s) in the activation of bicycle nitroimidazoles and in the physiology of Mycobacterium tuberculosis. ScholarBank@NUS Repository.
Abstract: The bicyclic 4-nitroimidazoles PA-824 and OPC-67683 that are currently in Phase II clinical development represent a promising novel class of therapeutics for Tuberculosis (TB). Both compounds are pro-drugs that are reductively activated within Mycobacterium tuberculosis, the causative organism of TB. PA-824 as a potential anti-TB agent has many attractive characteristics - most notably its novel mechanism of action, activity against aerobic replicating and hypoxic non-replicating mycobacterium, activity in vitro against drug-resistant clinical isolates, and activity as both a potent bactericidal and a sterilizing agent in mice. While PA-824 was optimized for its aerobic cellular activity, its anaerobic activity correlated with the amount of nitric oxide (NO) generated when the pro-drug was reduced by an Mtb deazaflavin cofactor (F420) dependent nitroreductase (Ddn). The physiological role of both F420 and the activating enzyme Ddn in Mtb is unknown. This thesis delves into two areas that are in line with developing drugs against latent TB and in unravelling novel Mtb `targets¿ for discovery of therapeutics against drug resistant Mtb.
URI: http://scholarbank.nus.edu.sg/handle/10635/35844
Appears in Collections:Ph.D Theses (Open)

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