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Selectivity of TMC207 towards mycobacterial ATP synthase compared with that towards the eukaryotic homologue.

ABSTRACT: 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.

SUBMITTER: Haagsma AC

PROVIDER: S-EPMC2650532 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Selectivity of TMC207 towards mycobacterial ATP synthase compared with that towards the eukaryotic homologue.

Haagsma Anna C AC Abdillahi-Ibrahim Rooda R Wagner Marijke J MJ Krab Klaas K Vergauwen Karen K Guillemont Jerome J Andries Koen K Lill Holger H Koul Anil A Bald Dirk D

Antimicrobial agents and chemotherapy 20081215 3

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 syn ...[more]

PMID: 19075053

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