Synthesis and Characterization of Amino Acid Derived Small Molecule Inhibitors of Bacterial 5'Methylthioadenosine / S-Adenosylhomocysteine Nucleosidase (MTN)

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) for E. coli O157:H7 MTN via the condensation of p -toluidine with various amino acids. Computational studies will be used to explore the interaction of these SMIs with the MTN active site, as well as with potential allosteric locations. The ability of these molecules to exert an anti-MTN effect in vitro will be explored.