Date

Thursday 24 Apr 2025

Time

10:00 - 10:30

Location

EM117

The rise of antibiotic resistance, particularly in ESKAPEE pathogens such as Methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii, creates an urgent need for the development of novel antibacterial inhibitors. Covalent inhibitors present a promising class of antibiotics due to their ability to form irreversible bonds with bacterial targets, offering sustained inhibition and potentially overcoming resistance mechanisms. This study focuses on developing covalent inhibitors targeting arginine residues in bacteria. Three compounds were synthesized with an arginine-directed warhead and an alkyne click handle for further diversification. A diverse library of compounds was synthesized with these probes using copper catalysed azide alkyne cycloadditions, followed by direct-to-biology screening against A. baumannii, Methicillin-Resistant Staphylococcus aureus, Escherichia coli, and LPS-deficient E. coli. Eight compounds demonstrated antibacterial activity, with two showing activity in both Methicillin-Resistant Staphylococcus aureus and LPS-deficient E. coli. To establish that a covalent interaction was the reason for the antimicrobial activity, control compounds lacking the reactive warhead were synthesized. A minimum inhibitory concentration assay confirmed the potency of the active compounds and revealed that a covalent interaction might be crucial for their antibacterial activity. A hemolysis assay demonstrated that the activity was not caused by cytotoxicity but rathervia uptake into the cell. Overall, this study demonstrates that arginine-targeting covalent inhibitors are excellent starting points for novel antibiotic development.