Susceptibility of Mycobacterium tuberculosis Cytochrome bd Oxidase Mutants to Compounds Targeting the Terminal Respiratory Oxidase, Cytochrome c

Atica Moosa; Dirk A Lamprecht; Kriti Arora; Clifton E Barry 3rd; Helena I M Boshoff; Thomas R Ioerger; Adrie J C Steyn; Valerie Mizrahi; Digby F Warner

doi:10.1128/AAC.01338-17

Susceptibility of Mycobacterium tuberculosis Cytochrome bd Oxidase Mutants to Compounds Targeting the Terminal Respiratory Oxidase, Cytochrome c

Antimicrob Agents Chemother. 2017 Sep 22;61(10):e01338-17. doi: 10.1128/AAC.01338-17. Print 2017 Oct.

Authors

Atica Moosa¹, Dirk A Lamprecht², Kriti Arora³, Clifton E Barry 3rd^{3

4}, Helena I M Boshoff³, Thomas R Ioerger⁵, Adrie J C Steyn^{2

6

7}, Valerie Mizrahi^{1

4}, Digby F Warner^{8

4}

Affiliations

¹ MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Department of Pathology, University of Cape Town, Cape Town, South Africa.
² Africa Health Research Institute, Durban, South Africa.
³ Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
⁴ Institute of Infectious Disease & Molecular Medicine, University of Cape Town, Cape Town, South Africa.
⁵ Department of Computer Science and Engineering, Texas A&M University, College Station, Texas, USA.
⁶ Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁷ Centres for AIDS Research and Free Radical Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁸ MRC/NHLS/UCT Molecular Mycobacteriology Research Unit, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Department of Pathology, University of Cape Town, Cape Town, South Africa [email protected].

Abstract

We deleted subunits I (cydA) and II (cydB) of the Mycobacterium tuberculosis cytochrome bd menaquinol oxidase. The resulting ΔcydA and ΔcydAB mutants were hypersusceptible to compounds targeting the mycobacterial bc₁ menaquinol-cytochrome c oxidoreductase and exhibited bioenergetic profiles indistinguishable from strains deficient in the ABC-type transporter, CydDC, predicted to be essential for cytochrome bd assembly. These results confirm CydAB and CydDC as potential targets for drugs aimed at inhibiting a terminal respiratory oxidase implicated in pathogenesis.

Keywords: TB drug discovery; electron transport chain; extracellular flux analysis; mycobacterial respiration; oxidative phosphorylation.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Antitubercular Agents / pharmacology
Cytochromes c / drug effects*
Drug Discovery
Electron Transport Complex IV / drug effects*
Electron Transport Complex IV / genetics*
Genome, Bacterial / genetics
Microbial Sensitivity Tests
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / genetics*
Oxidative Phosphorylation / drug effects
Oxygen / metabolism
Oxygen Consumption / genetics
Sequence Deletion / genetics

Substances

Antitubercular Agents
Cytochromes c
menaquinol oxidase
Electron Transport Complex IV
Oxygen