Mycobacterium tuberculosis is a bacterium responsible for causing millions of global tuberculosis cases annually. To combat high tuberculosis incidence, prevalence, and drug resistance, new antibiotics are essential. The rv3802c gene is a member of a gene cluster from rv3799c to rv3804c, which is involved in mycolic acid biosynthesis and is invariant in all mycobacteria. While enzymatic roles for most of this cluster’s encoded enzymes have been elucidated, not much is yet known about the rv3802c gene product beyond its thioesterase and phospholipase activity. We recently solved the first crystal structure of the M. tuberculosis Rv3802, allowing for proposal of an enzymatic mechanism of hydrolysis and visualization of an expansive, hydrophobic substrate binding site. Tetrahydrolipstatin, a prominent anti-obesity drug, has been shown to reversibly inhibit Rv3802. This presentation showcases the solved protein structure of Rv3802 and tetrahydrolipstatin at 3.5 Å. Additionally, we aimed to identify and evaluate other potential inhibitors against Rv3802. Previously, a preliminary assay using resorufin butyrate as the substrate was employed in inhibition studies with tetrahydrolipstatin. A new second generation assay with 4-methylumbelliferyl heptanoate has been introduced and used for fragment-based drug discovery evaluations. New leads on triazole-containing urea derivatives, following fluorometric-based assays, mass spectrometry, and X-ray crystallographic studies, shall also be presented. Ultimately, this research continues to advance tuberculosis drug discovery efforts towards Rv3802.

Probing the Mycobacterium tuberculosis Rv3802 with covalent and non-covalent inhibitors

2019 Spring National Meeting

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