A Small Molecule Inhibitor of Trans-Translation Synergistically Interacts with Cathelicidin Antimicrobial Peptides to Impair Survival of Staphylococcus aureus

Staphylococcus aureus is a leading cause of infection in the US and, due to the rapid development of resistance, new antibiotics are constantly needed. Trans -translation is a particularly promising antibiotic target because it is conserved in many bacterial species, is critical to bacterial survival, and is unique among prokaryotes. We have investigated the potential of KKL-40, a small molecule inhibitor of trans -translation, and find that it inhibits both methicillin-susceptible and methicillin-resistant strains of S. aureus . KKL-40 is also effective against Gram-positive pathogens including a vancomycin-resistant strain of Enterococcus faecalis , Bacillus subtilis and Streptococcus pyogenes , although its performance with Gram-negatives is mixed. KKL-40 synergistically interacts with the human antimicrobial peptide LL-37, a member of the cathelicidin family, to inhibit S . aureus but not other antibiotics tested including daptomycin, kanamycin or erythromycin. KKL-40 is not cytotoxic to HeLa cells at concentrations that are 100-fold greater than the effective MIC. We also find that S. aureus develops minimal resistance to KKL-40 even after multi-day passage in sub-lethal concentrations. Therefore, trans -translation inhibitors could be a particularly promising drug target against S. aureus , not only because of their ability to inhibit bacterial growth, but also because of their potential to simultaneously render S. aureus more susceptible to host antimicrobial peptides.