Infectious disease currently accounts for approximately one-third of the annual worldwide mortality and presents a pressing threat to the health and well-being of the global population. The challenge of infectious disease is compounded by a continued emergence of drug resistant and multiple-drug resistant microorganisms which, in turn, serves to underscore the need to develop novel antibiotics that are both selective and safe. One potential target for new antimicrobial therapies is 5’methylthioadenosine / S-adenosylhomocysteine nucleosidase (MTN). This enzyme is unique to microorganisms and plays a central role in processes associated with bacterial quorum sensing, including the expression of drug resistance, biofilm formation, and exotoxin production. As part of this project, we have synthesized and characterized a library of small molecule inhibitors (SMIs) of MTN via the condensation of p-tolulidine with various amino acids. The ability of these molecules to exert an anti-MTN effect in vitro has been explored.

Design, Synthesis, and Evaluation of Next-Generation Small Molecule Inhibitors of 5’Methylthioadenosine / S-Adenosylhomocysteine Nucleosidase (MTN)