Synthesis and Characterization of Next-Generation Adenine-Based Inhibitors of Bacterial MTN

Faculty Mentor Information

John Thurston, Ken Cornell

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, underscores 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. Here, we describe the use of copper-catalyzed, azo/alkyne "click" reactions to synthesize a series of non-hydrolyzable small molecule inhibitors (SMIs) from the building block 9-(prop-2-yn-1-yl)-9H-purin-6-amine. The SMIs developed in this study are designed to mimic the transition-state structure of the native substrate and are anticipated to function as competitive inhibitors of the target enzyme. The ability of the SMIs to exert an anti-MTN effect in vitro has been explored.

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Synthesis and Characterization of Next-Generation Adenine-Based Inhibitors of Bacterial 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, underscores 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. Here, we describe the use of copper-catalyzed, azo/alkyne "click" reactions to synthesize a series of non-hydrolyzable small molecule inhibitors (SMIs) from the building block 9-(prop-2-yn-1-yl)-9H-purin-6-amine. The SMIs developed in this study are designed to mimic the transition-state structure of the native substrate and are anticipated to function as competitive inhibitors of the target enzyme. The ability of the SMIs to exert an anti-MTN effect in vitro has been explored.