Drug target binding kinetics especially residence time plays a major role in determining the efficacy of drug in vivo. Increasing residence time leads to decrease in the drug dosage as well as decreasing toxicity. (LpxC) is a Zn<sup>2+</sup> deacetylase that is essential for the survival of most pathogenic Gram-negative bacteria. Because LpxC catalyzes the committed step in the biosynthesis of lipid A, an essential molecule for bacterial cell survival, it is a prime target for the development of novel antibiotics. Compounds with longer residence time can achieve the same efficacy at lower doses thereby potentially improving drug safety. The current goal of this research is to design and synthesize LpxC inhibitors with long residence time while maintaining optimized PK properties and biological activity. A detailed study of Structure activity relationships (SAR) and Structure kinetic relationships (SKR) of LpxC inhibitors will inform on the structural basis for the discovery of novel LpxC inhibitors with long residence time and long Post antibiotic effect (PAE).

Time dependent inhibition of LpxC

ACS Spring Meeting 2021

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