Abstract
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.
Highlights
Tuberculosis causes approximately 2 million deaths per year and an estimated 1/3 of the world population harbors Mycobacterium tuberculosis in a dormant or latent form [1,2]
We investigated the effect of the proton motive force on ATP synthesis inhibition by TMC207
TMC207 may interfere with ATP synthesis by competing with protons for the same binding site on ATP synthase
Summary
Tuberculosis causes approximately 2 million deaths per year and an estimated 1/3 of the world population harbors Mycobacterium tuberculosis in a dormant or latent form [1,2]. To counteract development of drug-resistant strains and to shorten tuberculosis treatment the discovery of new drugs, validation of new target proteins, and understanding of drug/target interactions are essential [6,7,8]. The diarylquinoline TMC207 (Figure 1A) is a highly promising candidate for treatment of drug-resistant tuberculosis and for shortening of tuberculosis treatment [10,11,12]. TMC207 acts on a novel target, mycobacterial ATP synthase [13] and is highly active on replicating as well as on dormant mycobacteria [14,15]. TMC207 acts in a highly selective manner, with only minimal effect on human ATP synthase and only minor side effects in human patients [10,16,17]
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