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Probing the Interaction of the Diarylquinoline TMC207 with Its Target Mycobacterial ATP Synthase

Infections with Mycobacterium tuberculosis are substantially increasing on a worldwide scale and new antibiotics are urgently needed to combat concomitantly emerging drug-resistant mycobacterial strains. The diarylquinoline TMC207 is a highly promising drug candidate for treatment of tuberculosis. T...

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Autores principales: Haagsma, Anna C., Podasca, Ioana, Koul, Anil, Andries, Koen, Guillemont, Jerome, Lill, Holger, Bald, Dirk
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157398/
https://www.ncbi.nlm.nih.gov/pubmed/21858172
http://dx.doi.org/10.1371/journal.pone.0023575
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author Haagsma, Anna C.
Podasca, Ioana
Koul, Anil
Andries, Koen
Guillemont, Jerome
Lill, Holger
Bald, Dirk
author_facet Haagsma, Anna C.
Podasca, Ioana
Koul, Anil
Andries, Koen
Guillemont, Jerome
Lill, Holger
Bald, Dirk
author_sort Haagsma, Anna C.
collection PubMed
description Infections with Mycobacterium tuberculosis are substantially increasing on a worldwide scale and new antibiotics are urgently needed to combat concomitantly emerging drug-resistant mycobacterial strains. The diarylquinoline TMC207 is a highly promising drug candidate for treatment of tuberculosis. This compound kills M. tuberculosis by binding to a new target, mycobacterial ATP synthase. In this study we used biochemical assays and binding studies to characterize the interaction between TMC207 and ATP synthase. We show that TMC207 acts independent of the proton motive force and does not compete with protons for a common binding site. The drug is active on mycobacterial ATP synthesis at neutral and acidic pH with no significant change in affinity between pH 5.25 and pH 7.5, indicating that the protonated form of TMC207 is the active drug entity. The interaction of TMC207 with ATP synthase can be explained by a one-site binding mechanism, the drug molecule thus binds to a defined binding site on ATP synthase. TMC207 affinity for its target decreases with increasing ionic strength, suggesting that electrostatic forces play a significant role in drug binding. Our results are consistent with previous docking studies and provide experimental support for a predicted function of TMC207 in mimicking key residues in the proton transfer chain and blocking rotary movement of subunit c during catalysis. Furthermore, the high affinity of TMC207 at low proton motive force and low pH values may in part explain the exceptional ability of this compound to efficiently kill mycobacteria in different microenvironments.
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spelling pubmed-31573982011-08-19 Probing the Interaction of the Diarylquinoline TMC207 with Its Target Mycobacterial ATP Synthase Haagsma, Anna C. Podasca, Ioana Koul, Anil Andries, Koen Guillemont, Jerome Lill, Holger Bald, Dirk PLoS One Research Article Infections with Mycobacterium tuberculosis are substantially increasing on a worldwide scale and new antibiotics are urgently needed to combat concomitantly emerging drug-resistant mycobacterial strains. The diarylquinoline TMC207 is a highly promising drug candidate for treatment of tuberculosis. This compound kills M. tuberculosis by binding to a new target, mycobacterial ATP synthase. In this study we used biochemical assays and binding studies to characterize the interaction between TMC207 and ATP synthase. We show that TMC207 acts independent of the proton motive force and does not compete with protons for a common binding site. The drug is active on mycobacterial ATP synthesis at neutral and acidic pH with no significant change in affinity between pH 5.25 and pH 7.5, indicating that the protonated form of TMC207 is the active drug entity. The interaction of TMC207 with ATP synthase can be explained by a one-site binding mechanism, the drug molecule thus binds to a defined binding site on ATP synthase. TMC207 affinity for its target decreases with increasing ionic strength, suggesting that electrostatic forces play a significant role in drug binding. Our results are consistent with previous docking studies and provide experimental support for a predicted function of TMC207 in mimicking key residues in the proton transfer chain and blocking rotary movement of subunit c during catalysis. Furthermore, the high affinity of TMC207 at low proton motive force and low pH values may in part explain the exceptional ability of this compound to efficiently kill mycobacteria in different microenvironments. Public Library of Science 2011-08-17 /pmc/articles/PMC3157398/ /pubmed/21858172 http://dx.doi.org/10.1371/journal.pone.0023575 Text en Haagsma et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Haagsma, Anna C.
Podasca, Ioana
Koul, Anil
Andries, Koen
Guillemont, Jerome
Lill, Holger
Bald, Dirk
Probing the Interaction of the Diarylquinoline TMC207 with Its Target Mycobacterial ATP Synthase
title Probing the Interaction of the Diarylquinoline TMC207 with Its Target Mycobacterial ATP Synthase
title_full Probing the Interaction of the Diarylquinoline TMC207 with Its Target Mycobacterial ATP Synthase
title_fullStr Probing the Interaction of the Diarylquinoline TMC207 with Its Target Mycobacterial ATP Synthase
title_full_unstemmed Probing the Interaction of the Diarylquinoline TMC207 with Its Target Mycobacterial ATP Synthase
title_short Probing the Interaction of the Diarylquinoline TMC207 with Its Target Mycobacterial ATP Synthase
title_sort probing the interaction of the diarylquinoline tmc207 with its target mycobacterial atp synthase
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3157398/
https://www.ncbi.nlm.nih.gov/pubmed/21858172
http://dx.doi.org/10.1371/journal.pone.0023575
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