SBIR-STTR Award

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, we will 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 currently no 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 combination therapies approved for clinical usage.

Thesaurus Terms:
Binding;Binding (Molecular Function);Chemicals;Clinic;Clinical;Combined Modality Therapy;Communicable Diseases;Complex;Data;Development;Disease;Disorder;Drug Design;Drug Resistance;Enzyme Antagonist;Enzyme Inhibitor;Enzyme Inhibitor Agent;Enzyme Inhibitor Drugs;Enzyme Inhibitors;Enzymes;Goals;Grant;Human;In Vitro;Infection;Infectious Agent;Infectious Disease Pathway;Infectious Diseases;Infectious Diseases And Manifestations;Infectious Disorder;Lead;Lytotoxicity;M. Tuberculosis Infection;M.Tuberculosis Infection;Mtb Infection;Malaria;Man (Taxonomy);Methods;Modern Man;Molecular Interaction;Mtb Infection [{C0041296}];Multimodal Therapy;Multimodal Treatment;Multimodality Treatment;Mycobacterium Tuberculosis (Mtb) Infection;Mycobacterium Tuberculosis Infection;Nmr Spectroscopy;Organism;Paludism;Pathway Interactions;Pb Element;Phase;Plasmodium Infections;Risk;Screening Procedure;Single Crystal Diffraction;Structure;Tuberculosis;X Ray Crystallographies;X-Ray Crystallography;X-Ray Diffraction Crystallography;X-Ray/Neutron Crystallography;Xray Crystallography;Base;Combat;Combination Therapy;Combined Modality Treatment;Combined Treatment;Cytotoxicity;Design;Designing;Developmental;Disease/Disorder;Disseminated Tb;Disseminated Tuberculosis;Drug Resistant;Heavy Metal Pb;Heavy Metal Lead;In Vivo;Infection Due To Mycobacterium Tuberculosis;Infectious Organism;Inhibitor;Inhibitor/Antagonist;Isoprenoid;Living System;Microbial;Multimodality Therapy;Novel;Nuclear Magnetic Resonance Spectroscopy;Pathogen;Pathway;Potency Testing;Resistance Strain;Resistance To Drug;Resistant Strain;Resistant To Drug;Screening;Screenings;Small Molecule;Success;Tuberculous Spondyloarthropathy