A virtual screening approach based upon a combination of docking and pharmacophore methods was utilized on a library of 1.4 million molecules to identify novel antimicrobial agents, which may potentially act via inhibition of the caseinolytic protease. Using this method, compound 6 was found to be bactericidal against three staphylococcal species (minimum inhibitory concentration (MIC)=4–16 μg/mL). Further, subsequent structural optimization of 6 led to the identification of compound 24, which was shown to be the most potent analog within the series (MIC=4 μg/mL) and outperforming the antibiotic controls for two of the staphylococcal species. The newly discovered antimicrobial agent (24) demonstrated excellent in silico ADME properties and was non‐toxic when tested on two human skin cell lines. As such, compound 24 has the potential for use as a lead molecule in the development of a novel class of antimicrobial agents.