In an effort to discover new leads against high-priority pathogens, a small array of diarylimidazoles was screened using the Community for Open Antimicrobial Drug Discovery (CO-ADD) platform, which profiled the compounds against the ESKAPE pathogens Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA) and the fungi Candida neoformans and C. albicans. Of the 18 compounds tested (at 32 μg/mL), 15 showed >90% growth inhibition activity against MRSA but not the other pathogens (Figures and, Supplementary Information -Biology). MRSA is a gram-positive pathogenic bacterium that was designated a high-priority pathogen by the WHO. 1d AMR was one of the greatest public health concerns prior to the COVID-19 pandemic; only MRSA infections increased by 13% from 2019 to 2020. 10 Given the potential public health benefits (particularly of narrow-spectrum antibiotics on host health, we decided to pursue hit-to-lead optimization of this series, which is exemplified by OSA_822 i (MRSA active) and OSA_812 (MRSA inactive) shown in Figure .