Abstract Title

Novel Oxadizaole-based Transition State Analogs of Enzyme 5’-Methylthioadenosine / S-Adenosylhomocysteine Nucleosidase

Abstract

The enzyme 5’-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTN) plays a central role in the regulation of microbial population-dependent processes. These processes include the upregulation and expression of drug-resistant phenotypes, biofilm formation, and exotoxin production. Taking inspiration from the structure of the MTN-substrate transition state, we have designed, synthesized, and characterized a series of novel small molecule inhibitors (SMIs) of MTN, using an oxadiazole structural motif as a common scaffold. The ability of these SMIs to exert an anti-MTN effect in vitro has been explored using UV-Vis Spectrophotometry. This process utilizes the different UV absorbances of Methylthioadenosine and adenosine, in conjunction with Beer’s Law, to determine a quantitative measure for enzyme-inhibitor binding. That measure, the Ki value, can relay information regarding the type and degree of inhibition that a given SMI has on MTN. If any SMIs prove to be effective inhibitors of the MTN enzyme, they possess the potential to become antibiotics that treat a variety of antibiotic-resistant bacterial strains.

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Novel Oxadizaole-based Transition State Analogs of Enzyme 5’-Methylthioadenosine / S-Adenosylhomocysteine Nucleosidase

The enzyme 5’-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTN) plays a central role in the regulation of microbial population-dependent processes. These processes include the upregulation and expression of drug-resistant phenotypes, biofilm formation, and exotoxin production. Taking inspiration from the structure of the MTN-substrate transition state, we have designed, synthesized, and characterized a series of novel small molecule inhibitors (SMIs) of MTN, using an oxadiazole structural motif as a common scaffold. The ability of these SMIs to exert an anti-MTN effect in vitro has been explored using UV-Vis Spectrophotometry. This process utilizes the different UV absorbances of Methylthioadenosine and adenosine, in conjunction with Beer’s Law, to determine a quantitative measure for enzyme-inhibitor binding. That measure, the Ki value, can relay information regarding the type and degree of inhibition that a given SMI has on MTN. If any SMIs prove to be effective inhibitors of the MTN enzyme, they possess the potential to become antibiotics that treat a variety of antibiotic-resistant bacterial strains.