Fragment based inhibitor discovery of the MEP pathway in infectious organisms.

DESCRIPTION (provided by applicant): We will apply nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography to study enzymes from the methyl erythritol isoprenoid (MEP) biosynthetic pathway, which is essential in multiple pathogens and absent in humans. Identification and biophysical characterization of fragments which bind to MEP targets will generate data for the rational design of small molecule leads for MEP enzymatic inhibition. Through iterative synthesis and structure determination, wewill develop these leads into novel compounds capable of binding MEP enzymes from a variety of infectious disease organisms. Success in this endeavor would lead to a Phase II proposal for focused synthesis and in vitro/in vivo potency testing to prove efficacy and advance these compounds closer to the clinic. The ultimate goal of this project is the development of novel treatments for those infected with drug-resistant strains of malaria, tuberculosis, and other microbial infections, as there are currentlyno MEP pathway inhibitor combination therapies approved for clinical usage PUBLIC HEALTH RELEVANCE: This project proposes to utilize biophysical methods to discover lead compounds that bind to enzymes from the methyl erythritol isoprenoid (MEP) biosynthetic pathway. The ultimate goal of this project is the development of novel treatments for those infected with drug-resistant strains of malaria, tuberculosis, and other microbial infections, as there are currently no MEP pathway inhibitor combinationtherapies approved for clinical usage.