Abstract Title

Progress Towards the Development of Novel, Non-hydrolyzable Bacterial MTN Inhibitors

Disciplines

Enzymes and Coenzymes | Medical Microbiology | Nucleic Acids, Nucleotides, and Nucleosides | Organic Chemicals

Abstract

Infectious disease, which currently accounts for approximately one-third of the annual worldwide mortality, presents a real and pressing threat to the health and well-being of the global population. This challenge is compounded by the increasing rate of emergence of drug resistant, and multiple-drug resistant microbial infections, which further underscores the continued need to develop new antibiotics that are both selective and safe. One potential target for antimicrobial therapies is 5' Methylthioadenosine /S-adenosylhomocysteine nucleosidase (MTN), an enzyme that is unique to microorganisms and which is known to play a central role in processes associated with bacterial quorum sensing such as drug resistance, biofilm formation, and the expression of virulence. We are investigating the synthesis of non-hydrolysable, nucleoside analogs that contain nitrogen-based functional groups. The structure of these compounds has been tailored to exploit the negative charge that is known to be present in the MTN active site. We anticipate that these potential inhibitors will exhibit both a high binding affinity and specificity for MTN, through favorable electrostatic interactions.

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Progress Towards the Development of Novel, Non-hydrolyzable Bacterial MTN Inhibitors

Infectious disease, which currently accounts for approximately one-third of the annual worldwide mortality, presents a real and pressing threat to the health and well-being of the global population. This challenge is compounded by the increasing rate of emergence of drug resistant, and multiple-drug resistant microbial infections, which further underscores the continued need to develop new antibiotics that are both selective and safe. One potential target for antimicrobial therapies is 5' Methylthioadenosine /S-adenosylhomocysteine nucleosidase (MTN), an enzyme that is unique to microorganisms and which is known to play a central role in processes associated with bacterial quorum sensing such as drug resistance, biofilm formation, and the expression of virulence. We are investigating the synthesis of non-hydrolysable, nucleoside analogs that contain nitrogen-based functional groups. The structure of these compounds has been tailored to exploit the negative charge that is known to be present in the MTN active site. We anticipate that these potential inhibitors will exhibit both a high binding affinity and specificity for MTN, through favorable electrostatic interactions.