Antimicrobial Agents and Chemotherapy · 2008 · 221 citations · 18 references
Life SciencesMedicinal ChemistryPharmacologyAntimicrobial PharmacologyCellular MetabolismMitochondrial BiologyAntibacterial PharmacologyMitochondrial BiochemistryMitochondrial BioenergeticsMitochondrial MetabolismMitochondrial PhysiologyAtp Synthase InhibitionAtp Synthase MechanismMitochondrial Atp SynthaseMitochondrial Atp SynthesisMitochondrial Enzyme InhibitionMitochondrial TargetsMycobacterium Tuberculosis InfectionSensitivity
The diarylquinoline TMC207 kills Mycobacterium tuberculosis by specifically inhibiting ATP synthase. We show here that human mitochondrial ATP synthase (50% inhibitory concentration [IC(50)] of >200 microM) displayed more than 20,000-fold lower sensitivity for TMC207 compared to that of mycobacterial ATP synthase (IC(50) of 10 nM). Also, oxygen consumption in mouse liver and bovine heart mitochondria showed very low sensitivity for TMC207. These results suggest that TMC207 may not elicit ATP synthesis-related toxicity in mammalian cells. ATP synthase, although highly conserved between prokaryotes and eukaryotes, may still qualify as an attractive antibiotic target.
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A Diarylquinoline Drug Active on the ATP Synthase of <i>Mycobacterium tuberculosis</i>
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Diarylquinolines target subunit c of mycobacterial ATP synthase
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