Abstract Title

Synthesis of Novel Adenine-Based Small Molecule Inhibitors of 5’-methylthioadenosine/S-adenosylhomocysteine Nucleosidase

Disciplines

Bacteria | Enzymes and Coenzymes | Organic Chemistry

Abstract

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. Using computational models as a guide, we have synthesized and characterized a series of potential nonhydrolyzable small molecule inhibitors (SMIs) from the building blocks 9-(2-aminoethyl)-9H-purin-6-amine, ethyl 2-(6-amino-9H-purin-9-yl)acetate and 9-(prop-2-yn-1-yl)-9H-purin-6-amine. The ability of these molecules to exert an anti-MTN effect in vitro has been explored.

Comments

Poster #W45

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Synthesis of Novel Adenine-Based Small Molecule Inhibitors of 5’-methylthioadenosine/S-adenosylhomocysteine Nucleosidase

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. Using computational models as a guide, we have synthesized and characterized a series of potential nonhydrolyzable small molecule inhibitors (SMIs) from the building blocks 9-(2-aminoethyl)-9H-purin-6-amine, ethyl 2-(6-amino-9H-purin-9-yl)acetate and 9-(prop-2-yn-1-yl)-9H-purin-6-amine. The ability of these molecules to exert an anti-MTN effect in vitro has been explored.