<i>Mycobacterium tuberculosis</i> (MTB) is the pathogen that causes tuberculosis (TB), a global epidemic and a leading cause of death worldwide, killing more people annually than HIV/AIDS. The increased occurrence of drug-resistant and multi-drug resistant infections can be largely attributed to the unique composition of the mycobacterial cell wall. These cell walls are lined with mycolic acids, derived from very long chained fatty acids (VLCFA). These components inhibit drug internalization and directly contribute to the pathogen’s virulence. In MTB, VLCFA are produced by an acyl carrier protein (ACP) dependent fatty acid synthase (FAS). Given that MTB FAS is essential to the mycobacteria's survival, and is distinct from many other bacterial FAS pathways in that it produces VLCFA, it is an ideal target for drug discovery and development. FAS produces mature fatty acids through iterative elongation and modification, and depends upon the formation of ACP-enzyme complexes that, due to their transient nature, have proven challenging to resolve using experimental structural biology. Though individual enzymatic components of FAS have been solved using x-ray crystallography, the lack of structural data regarding ACP-enzyme complexes have undoubtedly impeded efforts to rationally design small molecule inhibitors of mycolic acid synthesis. Here, we implement high-performance computing tools of molecular mechanic (MM) and dynamic (MD) simulations, in addition to solution state NMR titration studies to guide our structural understanding and drug discovery efforts.

Exploring the structural basis of biomolecular recognition in <i>Mycobacterium tuberculosis </i>type II fatty acid biosynthesis

ACS Spring 2022

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Exploring the structural basis of biomolecular recognition in Mycobacterium tuberculosis type II fatty acid biosynthesis