Date of Graduation
Master of Science in Chemistry
College of Arts and Sciences
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.
Bashir, Umyeena, "Covalent Inhibition of Enzyme Sortase A as a New Pathway Against Bacterial Resistance of Staphylococcus Aureus" (2023). Master's Theses. 1531.