Antibiotics were considered “Super Drugs” when first discovered in the 20th century. Since then, they have been used as first-line treatments for many bacterial infections. However, over the years, bacteria have developed resistance to these antimicrobial agents, thereby making treatment of antibiotic-resistant bacterial infections difficult. The caseinolytic protease proteolytic subunit (ClpP), a highly conserved serine protease, maintains bacterial homeostasis by controlled degradation of short-lived regulatory proteins as well as those that are misfolded or damaged. [1-2] In bacteria, the ClpP is also connected with pathogenesis, virulence and regulation of the cellular stress response. [3-5] Further, ClpP knockout strains of Staphylococcus aureus and Listeria monocytogenes are known to be responsible for reducing bacterial virulence, thereby attenuating infections in murine abscess models. [6-7]
A virtual screening approach 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, one compound was found to be bactericidal against three staphylococcal species (MIC) = 4–16 μg/mL. The subsequent structural optimization led to the identification of most potent analog within the series (MIC=4 μg/mL) which was found to be more potent than two antibiotics controls. The newly discovered antimicrobial agent demonstrated excellent in silico ADME properties and was non-toxic against two human cell lines. Therefore, identified compound has the potential for use as a lead molecule in the development of a novel class of antimicrobial agents.