Significance of a-Phenyl Group in MRSA Acetate Kinase Inhibitor AKIP at the Cellular Level — 95p — Olivia Valdez, Chun Wu

Mount Marty University, Yankton SD

Methicillin-resistant Staphylococcus aureus (MRSA) infections present a significant therapeutic challenge, necessitating the development of novel antibiotics. Our previous research identified acetate kinase (ACK), involved in energy metabolism, as a promising drug target. MRSA ACK was successfully cloned, expressed, purified, and characterized. High-throughput screening of inhibitors identified 38 potential candidates, with compound AKIP emerging as a lead inhibitor. Lineweaver-Burk plot assays demonstrated that AKIP is a competitive inhibitor of MRSA ACK with a Ki value of 2.9 μM. In this study, we assessed the antibacterial activity of AKIP using the Resazurin Microtitre Assay (REMA), revealing a minimum inhibitory concentration (MIC) of 70 μM. Additionally, we performed an initial structure-activity analysis, examining the role of an α-phenyl group. The data indicated that the α-phenyl group in AKIP enhanced its biochemical potency against MRSA ACK by 150-fold and its antibacterial activity against Staphylococcus aureus by 20 folds, likely due to improved hydrophobic interactions and increased bacterial membrane permeability. These results highlight the potential of AKIP as a narrow-spectrum antibiotic. Furthermore, the consistent action of AKIP at both molecular and cellular levels confirms MRSA acetate kinase (ACK) as a valid drug target for MRSA infections.

Mount Marty College
Dr. Chun Wu