Small Molecule Alanine Racemase Inhibitors as Novel Therapeutics for Tuberculosis

DESCRIPTION (provided by applicant): Once thought to be on the decline, tuberculosis (TB) still remains a major global health problem today. With an estimated eight million new cases and two million deaths annually, TB is the leading cause of death from an infectious disease. This situation is further exacerbated by the emergence of multi-drug resistant form of TB (MDR-TB), which is refractory to treatment by available antibiotics. New anti-tubercular drugs are urgently needed to combat MDR strains of Mycobacterium tuberculosis, a NIAID priority pathogen and the causative agent of MDR-TB. The objective of this proposal is to identify new drug candidates for the treatment of TB in general and MDR-TB in particular. To this end, we propose to identify small molecules that prevent the synthesis of the mycobacterial cell wall, a validated target that is essential for the survival of the bacterium. The specific target is the key bacterial enzyme, alanine racemase. This enzyme catalyzes the racemization of L-alanine to D-alanine, and provides the necessary D-alanine precursor for peptidoglycan synthesis. Using purified alanine racemase enzyme from M. tuberculosis, an existing enzymatic assay will be first optimized for high-throughput screening. The assay will then be used to screen proprietary natural and chemical compound libraries in search of small molecules that inhibit the catalytic activity of this enzyme. Hits identified in this manner will be critically evaluated for their ability to inhibit the growth of M. tuberculosis in culture. Successful completion of this project is anticipated to yield one or more compounds for further development as drug candidates for the treatment of TB and MDR-TB in ensuing Phase II studies.