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 ofKKL-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 inhibitbut 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 thatdevelops 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 rendermore susceptible to host antimicrobial peptides.