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Antimicrobial Agents and Chemotherapy, March 2009, p. 1290-1292, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01393-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Selectivity of TMC207 towards Mycobacterial ATP Synthase Compared with That towards the Eukaryotic Homologue{triangledown}

Anna C. Haagsma,1 Rooda Abdillahi-Ibrahim,1 Marijke J. Wagner,1 Klaas Krab,1 Karen Vergauwen,2 Jerome Guillemont,2 Koen Andries,2 Holger Lill,1 Anil Koul,2* and Dirk Bald1*

Department of Molecular Cell Biology, Faculty of Earth and Life Sciences, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands,1 Department of Antimicrobial Research, Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium2

Received 16 October 2008/ Returned for modification 13 November 2008/ Accepted 5 December 2008

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.

* Corresponding author. Mailing address for Dirk Bald: Department of Molecular Cell Biology, Faculty of Earth and Life Sciences, VU University Amsterdam, De Boelelaan 1085, 1081 HV Amsterdam, The Netherlands. Phone: 31-(0)20/5986991. Fax: 31-(0)20/5987136. E-mail: dirk.bald{at}falw.vu.nl. Mailing address for Anil Koul: Department of Antimicrobial Research, Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium Phone: 32-14603420. Fax: 32-14605403. E-mail: akoul{at}its.jnj.com

{triangledown} Published ahead of print on 15 December 2008.

Antimicrobial Agents and Chemotherapy, March 2009, p. 1290-1292, Vol. 53, No. 3
0066-4804/09/$08.00+0     doi:10.1128/AAC.01393-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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