NIH Reporter #5R01AI175342-03

Studies of lipoamide dehydrogenase tight binding inhibition in tuberculous and non-tuberculous mycobacteria

Research project funded by NIAID to develop and study tight binding inhibitors targeting mycobacterial enzymes to improve treatment of tuberculosis and non-tuberculous mycobacterial diseases.

Description

This project explores the chemical biology of Mtb Lpd, a validated target, to develop tight binding inhibitors (TBI) with improved efficacy, targeting multiple enzyme complexes in Mtb, including pyruvate dehydrogenase, α-ketoacid dehydrogenase, branched chain keto-acid dehydrogenase, and peroxynitrite reductase/peroxidase. The research aims to define the structural features responsible for tight binding, assess the role of target residence time (t1/2) in antibacterial activity, and develop analogs with enhanced in vivo efficacy. The study extends to NTM pathogens, including Mycobacterium avium and M. abscessus, to develop novel inhibitors.

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