Abstract Title
Development of Allosteric Inhibitors of 5’-Methylthioadenosine Nucleosidase (MTN)
Additional Funding Sources
The project described was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grant No. P20GM103408. We also acknowledge support from The Biomolecular Research Center at Boise State with funding from NIH NIGMS IDeA Grant No. P20GM109095, the National Science Foundation, Grant Nos. 0619793 and 0923535, the MJ Murdock Charitable Trust, and the Idaho State Board of Education.
Abstract
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 silicoscreening 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.
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 silicoscreening 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.
Comments
W13