Date of Graduation

Winter 12-31-2023

Document Type

Thesis

Degree Name

Master of Science in Chemistry

College/School

College of Arts and Sciences

Department/Program

Chemistry

First Advisor

Herman Nikolayevskiy

Second Advisor

Osasere Evbuomwan

Third Advisor

Michael Stevenson

Abstract

The continued rise of antibiotic-resistant bacteria, such as MRSA (methicillin-resistant Staphylococcus aureus), has made the discovery of novel antibiotics critical. While bacteriostatic and bactericidal antibiotics inevitably exert evolutionary pressure on bacteria to develop resistance, small molecules that target mechanisms of bacterial virulence present a promising alternative for treatment. Sortase A (Srt A), a cysteine protease of S. aureus, promotes bacterial virulence by covalently attaching proteins such as pilin to the bacterial surface, enabling bacterial adhesion to mammalian cells. Inhibitory studies of this enzyme have gained prominent interest as a new pathway for drug development since blocking this enzyme's ability to covalently attach pilin has been demonstrated to result in non-virulent bacteria. Recent results from Jaudzems et al. suggest that kojic acid-derived Michael acceptors are able to covalently inhibit the active-site cysteine residue of Srt A. Their validated but unoptimized hit, while moderately potent and nontoxic, suffers from aqueous instability and a lack of known structure-activity correlations. Toward this end, we have synthesized the Jaudzems structure, and evaluated its aqueous stability and inhibitory activity through NMR studies and enzyme kinetic assays. Additionally, by using the modern docking software Glide, we have computationally evaluated thousands of kojic acid derivatives, and have determined two general designs that focus on expanding into unoccupied regions of the Srt A active site. Future work will aim to develop a comprehensive structure-activity relationship on the basis of this computational model.

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