Department of Chemistry & Biochemistry, The University of Toledo
Tuberculosis is responsible for 1.5 million deaths each year. This is more than any other infectious disease caused by a single pathogen and no new first-line drugs for TB have entered the clinic in more than 50 years. My group combines structure/function relationship studies on Mycobacterium tuberculosis drug targets with library screening to improve the TB drug pipeline. The complementary tools of X-ray crystallography and enzyme kinetics/inhibition studies form the basis for identifying new TB-active compounds as well as the characterization of known anti-tubercular compounds with ambiguous mechanism-of-action. In particular, our studies have clarified the mechanism-of-action of Isoxyl, Thiacetazone, and Ebselen anti-bacterial activity against M. tuberculosis and shown that covalent modification of cysteine residues on bacterial protein targets is a valuable inhibitory mechanism. This presentation will discuss how we are applying that understanding and building upon those observations to develop second-generation, dual-function covalent inhibitors of mycobacterial mycolyltransferases. Preliminary results suggest that these compounds function synergistically with b-lactams in non-pathogenic mycobacteria and we are working to understand the mechanistic basis of this apparent synergy.