Prof. Peter Tonge, Stony Brook University

Drug-target residence time: In vivo antibacterial activity and in vivo imaging

Predicting drug efficacy in humans remains a major barrier to the development of novel chemotherapeutics, and we posit that the life-time of the drug-target complex (residence time) is of critical importance in determining in vivo drug activity. In support of this hypothesis, we have developed inhibitors of the enoyl-ACP reductase enzymes from Mycobacterium tuberculosis, Francisella tularensis, and Staphylococcus aureus, and have shown that the in vivo antibacterial activity of these compounds correlates with their residence time on the enzyme target. The structural changes that accompany drug-target complex formation are being probed by X-ray crystallography, NMR spectroscopy and MD simulations, and this information is being used to design inhibitors with longer residence times. We have also developed methods to introduce short-lived isotopes into these compounds and are using the labeled molecules to image drug distribution in vivo, with the long term goal of developing agents to non-invasively image bacterial load in humans.