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

doi:10.1128/AAC.01393-08

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 language	English
Pages (from-to)	1290-1292
Number of pages	3
Journal	Antimicrobial Agents and Chemotherapy
Volume	53
Issue number	3
DOIs	https://doi.org/10.1128/AAC.01393-08
Publication status	Published - Mar 2009

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title = "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 [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.",

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

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AU - Haagsma, A.C.

AU - Ibrahim, R.A.

AU - Wagner, M.J.

AU - Krab, K.

AU - Vergauwen, K

AU - Guillemont, J.

AU - Andries, K.

AU - Lill, H.

AU - Koul, A.

AU - Bald, D.

PY - 2009/3

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N2 - 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.

AB - 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.

U2 - 10.1128/AAC.01393-08

DO - 10.1128/AAC.01393-08

M3 - Article

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VL - 53

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EP - 1292

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

IS - 3

ER -

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

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