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

Abstract

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. trans-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 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-negative pathogens 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 higher than the effective MIC. We also find that S. aureus develops minimal resistance to KKL-40 even after multiday passage at sublethal 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.

New 1,3,4-oxadiazole compound with effective antibacterial and antibiofilm activity against Staphylococcus aureus

“…Huang et al . (2019) evaluated the oxadiazole compounds KKL‐35 and KKL‐40 against three S. aureus strains (Newman, MRSA252 and USA300). KKL‐35 had a MIC of 0·64 μg ml −1 against S. aureus USA300 and 1·28 μg ml −1 against S. aureus Newman and S. aureus MRSA252.…”

Trans-Translation Is an Appealing Target for the Development of New Antimicrobial Compounds

“…KKL-2098 targets helix 89 of 23S rRNA, but in a region not targeted by conventional antibiotics. It binds to a pocket adjacent to the peptidyl transfer center (PTC), without inhibiting canonical translation [68,76]. More recently, this result was confirmed by cryo-EM (EMDB with the accession code EMD-20121).…”

“…Considering that trans-translation is absent in eukaryotes, tmRNA-SmpB is an especially promising target for novel antibiotics. Obviously, when it is essential to the survival of pathogenic bacteria, the trans-translation machinery is an excellent specific target for use in developing molecules to kill bacteria directly [35,67,68]. When non-lethal, because alternative rescue factors can take over the rescue process, deletion of tmRNA and/or SmpB induces various phenotypes, including loss of virulence or loss of antibiotic tolerance [69][70][71][72].…”

The Potential of Human Peptide LL-37 as an Antimicrobial and Anti-Biofilm Agent

“…Serpin A1 primarily enhances the antimicrobial activities of LL-37 through the protection against endotoxins, and aiding in the suppression of bacterial proliferation [138]. KKL-40, a small-molecule inhibitor of trans-translation, causes a maladapted stress response in the bacteria to LL-37, thus increasing the bacteria's vulnerability to the peptide [200].…”