Texas A&M, USA
Molecular & Structural Biology
Developing inhibitors for Mycobacterium tuberculosis requires an understanding of the metabolic pathways required for survival and persistence of mycobacteria in the host. As part of my work to identify lead compounds that target CO2-dependent processes, a series of commercially available ACCase inhibitors were screened for activity against M. tuberculosis. Of these compounds, a number of Fops, Dims, and cyclohexanediones were found to be bactericidal (µM inhibitors). The compounds target the Acetyl CoA-caboxyltransferase domain, an enzyme that is essential for the conversion of acetyl-CoA to malonyl-CoA in the fatty acid biosynthesis pathway. Due to the homology between AccD6 (in M. tuberculosis and ACC in Cryptosporodium parvum, these compounds are believed to target acetyl-CoA Carboxylase in C. parvum. We have identified most potent compounds with low cytotoxicity have been found that inhibit Mtb, Cryptosporodium and Trypanosoma ACC’s. The compounds target the acetyl-CoA carboxylase (ACC) and have been developed using traditional medicinal chemistry coupled to structure-guided approaches. Several compounds were demonstrated to control infection in two murine models of cryptosporidiosis without evidence of toxicity. We use a homology model of the American trypanosome T. cruzi enzyme (TbACC) based on our crystal structure of M. tuberculosis ACC-AccD6. We have developed a novel series of inhibitors against American trypanosome, T. cruzi. Our lead molecules are quite potent, have good pharmacokinetics, and show no overt toxicity when administered to human cell lines or mice. Our best inhibitors approach the potency of benznidazole and are much safer. These studies take advantage of the closely related T. brucei as an experimental surrogate of T. cruzi, due to its advanced genetics and more defined growth conditions.