Development of Allosteric Inhibitors of 5’-Methylthioadenosine Nucleosidase (MTN)

One-third of the annual worldwide mortality is attributed to infectious disease. With the emergence of drug resistant and multi-drug resistant microbial infections, there is a pressing need to develop novel therapeutic agents. One potential target is 5’-Methylthioadenosine / S-adenosylhomocysteine nucleosidase (MTN), an enzyme unique to microorganisms, and not found in humans. MTN is essential to the methionine/purine salvage pathway, and is known to play a critical role in bacterial quorum sensing. As part of this project, we have explored the activity of 43 potential allosteric inhibitors of the E. coli MTN that were identified by in silico screening of a library of ~10,000 compounds for binding to an alternate site cleft. Many of these compounds are already FDA approved for use in treating other diseases. The inhibitors we identify will be further investigated for efficacy as antibiotics to treat bacterial and parasitic infections.