Mycobacterium tuberculosis is a bacterium responsible for causing millions of tuberculosis cases around the world each year. The virulence of this bacterium is attributed to its uniquely structured lipid bilayer cell wall, utilizing a highly ordered mycolic acid packing arrangement that increases protection against antibiotics. As tuberculosis incidence, drug resistance, and prevalence rates stay high, new antibiotics are in great need and demand. A conserved five-gene cluster starting from rv3799c to rv3804c encodes enzymes that play a central role in mycolic acids biosynthesis. As mycolic acids are important building blocks for the maintenance of the mycobacterial cell wall, inhibition of mycolic acid biosynthesis has been targeted by most first and second-line TB drugs. The enzymatic role, of most of the enzymes of the aforementioned gene cluster, is known, but the function of the Rv3802c gene product, outside of an identified general esterase activity, in cell wall biosynthesis is not known. The main goals of this project were to clone, express, purify, assay, and determine the crystallographic structure for recombinant Rv3802c to aid in the characterization of the cellular function. Using a newly developed fluorometric enzymatic assay, an inhibitor library was screened for Rv3802c inhibitory activity. Additionally, the X-ray crystal structure was solved to a resolution of 1.7 Å. The structure provides insights on structural dynamics required to promote substrate binding and affords the use of protein structural information for drug development efforts against the growing global detrimental impact of M. tuberculosis infection.

Structural, enzymatic, and inhibitory study of M. tuberculosis Rv3802c

253rd National Meeting (2017)

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