Features and Functional Importance of Key Residues of the Mycobacterium tuberculosis Cytochrome bd Oxidase

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 bc 1 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.

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Syntheses and Structure–Activity Relationships of N-Phenethyl-Quinazolin-4-yl-Amines as Potent Inhibitors of Cytochrome bd Oxidase in Mycobacterium tuberculosis

Applied Sciences ◽

10.3390/app11199092 ◽

2021 ◽

Vol 11 (19) ◽

pp. 9092

Author(s):

Sarah M. Hopfner ◽

Bei Shi Lee ◽

Nitin P. Kalia ◽

Marvin J. Miller ◽

Kevin Pethe ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Clinical Isolate ◽

Mycobacterium Bovis ◽

Energy Production ◽

Atp Depletion ◽

Structure Activity Relationships ◽

Mycobacterium Tuberculosis H37rv ◽

Cytochrome Bd ◽

Structure Activity ◽

Cytochrome Bd Oxidase

The development of cytochrome bd oxidase (cyt-bd) inhibitors are needed for comprehensive termination of energy production in Mycobacterium tuberculosis (Mtb) to treat tuberculosis infections. Herein, we report on the structure-activity-relationships (SAR) of 22 new N-phenethyl-quinazolin-4-yl-amines that target cyt-bd. Our focused set of compounds was synthesized and screened against three mycobacterial strains: Mycobacterium bovis BCG, Mycobacterium tuberculosis H37Rv and the clinical isolate Mycobacterium tuberculosis N0145 with and without the cytochrome bcc:aa3 inhibitor Q203 in an ATP depletion assay. Two compounds, 12a and 19a, were more active against all three strains than the naturally derived cyt-bd inhibitor aurachin D.

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A Mycobacterium tuberculosis Cytochrome bd Oxidase Mutant Is Hypersensitive to Bedaquiline

mBio ◽

10.1128/mbio.01275-14 ◽

2014 ◽

Vol 5 (4) ◽

Cited By ~ 48

Author(s):

Michael Berney ◽

Travis E. Hartman ◽

William R. Jacobs

Keyword(s):

Mycobacterium Tuberculosis ◽

Proton Pumping ◽

Major Drawback ◽

Content Type ◽

Cytochrome Bd ◽

New Drug ◽

Long Duration ◽

Bacterial Enzyme ◽

Drug Regimens ◽

Cytochrome Bd Oxidase

ABSTRACT The new medicinal compound bedaquiline (BDQ) kills Mycobacterium tuberculosis by inhibiting F1Fo-ATP synthase. BDQ is bacteriostatic for 4 to 7 days and kills relatively slowly compared to other frontline tuberculosis (TB) drugs. Here we show that killing with BDQ can be improved significantly by inhibiting cytochrome bd oxidase, a non-proton-pumping terminal oxidase. BDQ was instantly bactericidal against a cytochrome bd oxidase null mutant of M. tuberculosis, and the rate of killing was increased by more than 50%. We propose that this exclusively bacterial enzyme should be a high-priority target for new drug discovery. IMPORTANCE A major drawback of current TB chemotherapy is its long duration. New drug regimens with rapid killing kinetics are desperately needed. Our study demonstrates that inhibition of a nonessential bacterial enzyme greatly improves the efficacy of the latest TB drug bedaquiline and emphasizes that screening for compounds with synergistic killing mechanisms is a promising strategy.

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