Komodo-dragon cathelicidin-inspired peptides are antibacterial against carbapenem-resistant Klebsiella pneumoniae.

Abstract

Introduction. The rise of carbapenem-resistant enterobacteriaceae (CRE) is a growing crisis that requires development of novel therapeutics.Hypothesis. To this end, cationic antimicrobial peptides (CAMPs) represent a possible source of new potential therapeutics to treat difficult pathogens such as carbapenem-resistant Klebsiella pneumoniae (CRKP), which has gained resistance to many if not all currently approved antibiotics, making treatment difficult.Aim. To examine the anti-CRKP antimicrobial activity of the predicted cathelicidins derived from Varanus komodoensis (Komodo dragon) as well as synthetic antimicrobial peptides that we created.Methodology. We determined the minimum inhibitory concentrations of the peptides against CRKP. We also characterized the abilities of these peptides to disrupt the hyperpolarization of the bacterial membrane as well as their ability to form pores in the membrane.Results. We did not observe significant anti-CRKP activity for the predicted native Komodo cathelicidin peptides. We found that the novel peptides DRGN-6,-7 and -8 displayed significant antimicrobial activity against CRKP with MICs of 4-8 µg ml-1. DRGN-6 peptide was the most effective peptide against CRKP. Unfortunately, these peptides showed higher than desired levels of hemolysis, although in vivo testing in the waxworm Galleria mellonella showed no mortality associated with treatment by the peptide; however, CRKP-infected waxworms treated with peptide did not show an improvement in survival.Conclusion. Given the challenges of treating CRKP, identification of peptides with activity against it represents a promising avenue for further research. Given DRGN-6's similar level of activity to colistin, DRGN-6 is a promising template for the development of novel antimicrobial peptide-based therapeutics.