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

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