Infectious disease accounts for approximately one-third of annual worldwide mortality. In the past two decades, increasing rates of drug resistant, and multiple-drug resistant microbial infections underscore the urgent need to develop new antibiotics that are selective and safe. One potential target for novel antibiotics is the microbe specific 5' Methylthioadenosine /S-adenosylhomocysteine nucleosidase (MTN), an enzyme with a central role in nutrient salvage and synthesis of bacterial quorum sensing signals that govern processes such as drug resistance, biofilm formation, and the expression of virulence. As part of this work we have investigated the formation of novel non-hydrolysable nucleoside analogs to serve as MTN inhibitors. The compounds that are being developed as part of this project bear one or more methylene units between the ribose scaffold and the base component of the nucleoside molecule. This structural feature allows these molecules to mimic the later portion of the transition state found in the MTN catalyzed reaction pathway. The ultimate goal of this project will be to develop compounds that show both a high binding affinity and specificity for the bacterial enzyme.

Progress towards the development of novel late transition state MTN-specific C-nucleoside inhibitors