Dataset Information

Respiratory flexibility in response to inhibition of cytochrome C oxidase in Mycobacterium tuberculosis.

ABSTRACT: We report here a series of five chemically diverse scaffolds that have in vitro activities on replicating and hypoxic nonreplicating bacilli by targeting the respiratory bc1 complex in Mycobacterium tuberculosis in a strain-dependent manner. Deletion of the cytochrome bd oxidase generated a hypersusceptible mutant in which resistance was acquired by a mutation in qcrB. These results highlight the promiscuity of the bc1 complex and the risk of targeting energy metabolism with new drugs.

SUBMITTER: Arora K

PROVIDER: S-EPMC4249445 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Publications

Respiratory flexibility in response to inhibition of cytochrome C oxidase in Mycobacterium tuberculosis.

Arora Kriti K Ochoa-Montaño Bernardo B Tsang Patricia S PS Blundell Tom L TL Dawes Stephanie S SS Mizrahi Valerie V Bayliss Tracy T Mackenzie Claire J CJ Cleghorn Laura A T LA Ray Peter C PC Wyatt Paul G PG Uh Eugene E Lee Jinwoo J Barry Clifton E CE Boshoff Helena I HI

Antimicrobial agents and chemotherapy 20140825 11

We report here a series of five chemically diverse scaffolds that have in vitro activities on replicating and hypoxic nonreplicating bacilli by targeting the respiratory bc1 complex in Mycobacterium tuberculosis in a strain-dependent manner. Deletion of the cytochrome bd oxidase generated a hypersusceptible mutant in which resistance was acquired by a mutation in qcrB. These results highlight the promiscuity of the bc1 complex and the risk of targeting energy metabolism with new drugs. ...[more]

PMID: 25155596

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Project description:Mycobacterium tuberculosis depends on aerobic respiration for growth and utilizes an aa3-type cytochrome c oxidase for terminal electron transfer. Cytochrome c maturation in bacteria requires covalent attachment of heme to apocytochrome c, which occurs outside the cytoplasmic membrane. We demonstrate that in M. tuberculosis the thioredoxin-like protein Rv3673c, which we named CcsX, is required for heme insertion in cytochrome c. Inactivation of CcsX resulted in loss of c-type heme absorbance, impaired growth and virulence of M. tuberculosis, and induced cytochrome bd oxidase. This suggests that the bioenergetically less efficient bd oxidase can compensate for deficient cytochrome c oxidase activity, highlighting the flexibility of the M. tuberculosis respiratory chain. A spontaneous mutation in the active site of vitamin K epoxide reductase (VKOR) suppressed phenotypes of the CcsX mutant and abrogated the activity of the disulfide bond-dependent alkaline phosphatase, which shows that VKOR is the major disulfide bond catalyzing protein in the periplasm of M. tuberculosis.Mycobacterium tuberculosis requires oxygen for growth; however, the biogenesis of respiratory chain components in mycobacteria has not been explored. Here, we identified a periplasmic thioredoxin, CcsX, necessary for heme insertion into cytochrome c. We investigated the consequences of disrupting cytochrome c maturation (CCM) for growth and survival of M. tuberculosis in vitro and for its pathogenesis. Appearance of a second-site suppressor mutation in the periplasmic disulfide bond catalyzing protein VKOR indicates the strong selective pressure for a functional cytochrome c oxidase. The observation that M. tuberculosis is able to partially compensate for defective CCM by upregulation of the cytochrome bd oxidase exposes a functional role of this alternative terminal oxidase under normal aerobic conditions and during pathogenesis. This suggests that targeting both oxidases simultaneously might be required to effectively disrupt respiration in M. tuberculosis.

Dataset Information

Respiratory flexibility in response to inhibition of cytochrome C oxidase in Mycobacterium tuberculosis.

Publications

Respiratory flexibility in response to inhibition of cytochrome C oxidase in Mycobacterium tuberculosis.

Similar Datasets

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