Mycobacterium tuberculosis (Mtb) remains a potent threat, with particular risks presented to individuals bearing compromised immune systems or undergoing immunosuppressive treatment. This along with concerns over emerging drug resistance has heightened the awareness for the development of next generation anti-tubercular medicines. As part of a larger effort to expand Mtb drug discovery by targeting metabolic pathways essential to the mycobacterial life cycle, our laboratory has been exploring the biosynthesis of mycolic acids as a drug target. Although considerable effort toward understanding has emerged, we have taken a new approach by identifying mechanisms that target key protein-protein interactions involved in mycolic acid biosynthesis. In this program, we adapt carrier protein modification methods, developed in our laboratories, to prepare AcpM, the carrier protein involved long chain fatty acid extension in mycolic acid biosynthesis, bearing very-long chain fatty acid (VLCFA) analogs. These materials are used in conjunction with protein NMR methods to develop a detailed structural understanding of the mechanisms in which AcpM accommodates the production of VLCFAs. The overarching goal of this program is to identify key residues and pockets within AcpM that can be targeted for subsequent therapeutic development.
While once addressed, Mycobacterium tuberculosis (Mtb) has recently returned as a potential threat due to resistance and complications in immunosuppressed individuals. This program seeks to reveal new targets for therapy by exploring the discreet structural requirements of the enzymes and proteins involved in the biosynthesis of mycolic acids, a very long chain fatty acid found within the cell walls of mycobacteria including Mtb.
