Evaluation of the Antimicrobial Properties of a Natural Peptide from Vespa mandarinia Venom and Its Synthetic Analogues as a Possible Route to Defeat Drug-Resistant Microbes

SIMPLE SUMMARY: With the prevalence of antimicrobial resistance caused by drug abuse, severe infection currently remains an urgent global challenge. The antimicrobial peptides rich in wasp venom advance the development of new drugs to addressing this issue. A natural peptide from wasp venom was discovered with a great antimicrobial activity against Gram-positive bacteria both in vitro and in vivo. Meantime, by adapting for specific substitution of amino acid, the engineered peptide exhibited more potency and broader spectrum of antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria and yeast. ABSTRACT: Antimicrobial peptides (AMPs) from wasp venom have a good track record and potential for drug development as tools against development of antimicrobial resistance. Herein, the biological function and activity profile of peptide VM, which was discovered in the venom of the wasp, Vespa mandarinia, and several of its third-position substituted analogues, were investigated. VM had potent antimicrobial activity against Gram-positive bacteria and biofilm, and all modified peptides achieved the significant enhancement of these capacities. The various physicochemical properties of amino acids substituted in analogues, generated the different mechanisms of action of bacterial membrane disruption. VM-3K showed a maximum 8-fold enhancement of antibacterial activity against Gram-positive bacteria and also presented microbicidal properties against Gram-negative bacteria and fungi. This peptide also exhibited a high killing efficiency at low concentration and had a comparable selectivity index to VM. Furthermore, VM-3K produced a 90% survival of S. aureus-infected waxworms at a concentration of 5.656 mg/kg, at which concentration the natural template peptide only achieved 50% survival. This peptide also lacked short-term resistance generation. Thus, peptide VM-3K could be a promising broad-spectrum antimicrobial candidate for addressing the current antibiotic-resistant infection crisis. It is worth mentioning that this investigation on the relationship between peptide structure and mechanism of action could become an important aspect of drug research on short peptides.