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An F420 dependent anti-oxidant mechanism protects Mycobacterium against oxidative stress and bactericidal agents

Gurumurthy, Meera and Rao, Srinivasa P.S. and Manjunatha, Ujjini Havaldar and Rao, Martin and Mukharjee, Tathagata and Boshoff, Helena and Dick, Thomas and Barry, Clifton (2013) An F420 dependent anti-oxidant mechanism protects Mycobacterium against oxidative stress and bactericidal agents. Molecular Microbiology. ISSN 0950-382X

Abstract

Mycobacterium tuberculosis, an aerobic bacterium that persists intracellularly in host macrophages, has evolved diverse mechanisms to combat and survive oxidative stress. Here we show a novel F420 dependent anti-oxidant mechanism that protects mycobacterium against oxidative stress. Inactivation of fbiC gene in Mtb results in a cofactor F420 deficient mutant; Mtb F420- mutants are hypersensitive to oxidative stress and exhibit an enhanced reduction in NADH/NAD+ ratios upon treatment with menadione. In agreement with the recent hypothesis on oxidative stress being the common pathway resulting in cell death by bactericidal agents, F420- mutants are hypersensitive to mycobactericidal agents such as isoniazid and moxifloxacin. Further we show that Mtb Deazaflavin dependent nitroreductase (Ddn) and its two homologues Rv1261c and Rv1558 encode for an F420H2 dependent quinone reductase (Fqr) function. At the expense of F420H2, Fqr enzymes utilize menaquinone and ubiquinone analogues as efficient substrates catalyzing the formation of their respective dihydroquinones. Our results demonstrate that Ddn and its homologues catalyze an F420H2 specific obligate two electron reduction of endogenous quinones, thereby competing with the one electron reduction pathway and preventing the formation of harmful cytotoxic semiquinones. Fqr thus emerges as a new class of proteins that protects mycobacteria against oxidative stress and bactericidal agents. Further, these findings open up an avenue for the inhibition of F420 biosynthesis pathway or Fqr class as a mechanism to potentiate the action of bactericidal agents.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/8016

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