title: A Mycobacterium tuberculosis cytochrome bd oxidase mutant is hypersensitive to bedaquiline.
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.
authors.affiliation: Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, USA michael.berney@einstein.yu.edu jacobsw@hhmi.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Berney
authors.affiliation: Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Travis E
authors.initials: TE
authors.lastname: Hartman
authors.affiliation: Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, USA michael.berney@einstein.yu.edu jacobsw@hhmi.org.
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D003580:Cytochromes / Q000235:genetics*; D064687:Diarylquinolines / Q000494:pharmacology*; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics*
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D003580:Cytochromes; D064687:Diarylquinolines; C493870:bedaquiline; D010088:Oxidoreductases