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

A.C. Haagsma, R.A. Ibrahim, M.J. Wagner, K. Krab, K Vergauwen, J. Guillemont, K. Andries, H. Lill, A. Koul, D. Bald

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    Abstract

    The diarylquinoline TMC207 kills Mycobacterium tuberculosis by specifically inhibiting ATP synthase. We show here that human mitochondrial ATP synthase (50% inhibitory concentration [IC50] of >200 μM) displayed more than 20,000-fold lower sensitivity for TMC207 compared to that of mycobacterial ATP synthase (IC50 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.
    Original languageEnglish
    Pages (from-to)1290-1292
    Number of pages3
    JournalAntimicrobial Agents and Chemotherapy
    Volume53
    Issue number3
    DOIs
    Publication statusPublished - Mar 2009

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