Predicting drug efficacy in humans remains a major barrier to the development of novel chemotherapeutics. We propose that the life-time of the drug-target complex (residence time) is of critical importance for determining in vivo drug activity since drug and target are not at equilibrium in vivo. 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 and MD simulations, and this information is being used to rationally modulate residence time using site-directed mutagenesis and the synthesis of additional inhibitors. We are also exploring the factors that limit the impact of residence time on antibacterial activity at the cellular level.

Drug-target residence time: Correlating in vitro enzyme inhibition with in vivo antibacterial activity

245th National Meeting (2013)

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