Komodo-Dragon Inspired Cathelcidin Peptides Are Antibacterial Against Carbapenem-Resistant Klebsiella pneuonmiae
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Hitt, Christopher
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Abstract
The rise of carbapenem-resistant enterobacteriaceae (CRE) is a growing crisis that requires development of novel therapeutics. To this end, cationic antimicrobial peptides (CAMPs) represent a potential source of new potential therapeutics to treat difficult pathogens such as Klebsiella pneumoniae (CRKP), which has gained resistance to many if not all currently approved antibiotics making treatment difficult. In this paper we examined the anti-CRKP antimicrobial activity of the predicted cathelicidins derived from Varanus komodoensis (Komodo dragon) as well as synthetic antimicrobial peptides that we created. We did not observe significant anti-CRKP activity of for the predicted native Komodo cathelicidin peptides. We found significant antimicrobial activity of that the novel peptides DRGN-6, -7 and -8 were antimicrobial against CRKP with MICs between 4-8 μg/mL. DRGN-6 peptide was the most effective peptide against CRKP. We 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. After further testing, 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. 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.
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This thesis has been embargoed for 2 years. It will not be available until May 2022 at the earliest.
Keywords
Chimeric peptides, ESKAPE pathogens, Cationic antimicrobial peptides, Novel antimicrobials, Cathelicidins, Carbapenem resistant Klebsiella pneumoniae