Many drug candidates fail in clinical trials due to poor in vivo efficacy in humans. We speculate that our poor success rate at predicting in vivo drug efficacy stems from a reliance on in vitro assessments of drug activity that are performed at constant drug concentration (under equilibrium conditions), when in fact drug concentration is not constant in the human body. We thus propose that the kinetics of drug-target complex formation and breakdown is a critical factor in modulating drug action. In this proposal we will elucidate the molecular factors that dictate the impact of drug- target residence time on in vivo drug activity. These studies will focus on inhibitors of FabI, an enzyme drug-target from Mycobacterium tuberculosis, and LpxC, an enzyme drug target from Gram negative ESKAPE pathogens. We will quantitate the role that intracellular events such as target (re)synthesis, target degradation and target vulnerability have on the correlation between drug-target residence time and antibacterial activity determined as a function of drug concentration. This includes the prolongation of antibacterial activity following removal of drug from the system (the post-antibiotic effect). We will develop structure-kinetics relationships for the time-dependent inhibition of FabI and LpxC using a combination of structural and computational biology coupled with enzyme kinetics, and synthesize inhibitors of FabI and LpxC with extended target engagement. A mathematical model will be used that links drug-target kinetics and drug pharmacokinetics with predictions of antibacterial activity in whole cells and animal models of infection. Improved ability to predict in vivo drug action from in vitro parameters will have a dramatic impact on the discovery of new therapeutic agents.
Despite the enormous resources committed to the development of new drugs, many drug candidates fail in human clinical trials. Novel approaches are thus needed to improve our ability to develop new drugs. This project will integrate the kinetics of drug action into the drug discovery paradigm thereby improving the ability to predict drug efficacy in humans.
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