Bedaquiline Targets the ε Subunit of Mycobacterial F-ATP Synthase.
The tuberculosis drug bedaquiline inhibits mycobacterial F-ATP synthase by binding to its c subunit. Using the purified ε subunit of the synthase and spectroscopy, we previously demonstrated that the drug interacts with this protein near its unique tryptophan residue. Here, we show that replacement of ε's tryptophan with alanine resulted in bedaquiline hypersusceptibility of the bacteria. Overexpression of the wild-type ε subunit caused resistance. These results suggest that the drug also targets the ε subunit.
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Subhashri
S
Kundu
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Goran
G
Biukovic
School of Biological Sciences, Nanyang Technological University, Singapore.
Gerhard
G
Grüber
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore thomas_dick@nuhs.edu.sg.
Thomas
T
Dick
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D000409:Alanine / Q000235:genetics; D019943:Amino Acid Substitution; D000995:Antitubercular Agents / Q000494:pharmacology*; D064687:Diarylquinolines / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D058990:Molecular Targeted Therapy / Q000379:methods; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000235:genetics; D021122:Protein Subunits; D014364:Tryptophan / Q000235:genetics
D000995:Antitubercular Agents; D064687:Diarylquinolines; D004791:Enzyme Inhibitors; D021122:Protein Subunits; C493870:bedaquiline; D014364:Tryptophan; D000251:Adenosine Triphosphatases; D000409:Alanine