Antimicrobial Activity,Cytotoxicity And Trypsine Resistance Of Antimicrobial Peptide Polybia-MPⅡ And Its Analogs

Recently,the extensive use of antibiotics in medicine,agriculture and food industry has caused frequent emergency of multi-drug resistant microbe in the worldwide.The infection of drug-resistant microbe could cause millions of people to die every year,which seriously threatens the life and health of mankind.Therefore,it is urgent need to develop new drugs with novel action model to defend drug resistant pathogens.Antimicrobial peptides（AMPs）,were found in almost all forms of life such as human,animals,plants and microorganisms,with the broad spectrum of biological activities such as antifungal,antibacterial,antiviral,antitumor and immunomodulatory activity.It is difficult for microorganisms to develop resistance to AMPs because of their membrane disruption action mode.So AMPs are considered to be potential alternatives of traditional antibiotics.Polybia-MPⅡ（MPⅡ,INWLKLGKMVIDAL-NH₂）is a typical AMP from the venom of the social wasp Polybia paulista.It exhibited excellent antifungal,antitumor and antibacterial activity,however,it is sensitive to protease and has high hemolytic activity.In this study,we designed and synthesized a series of analogs（HMPⅡ,RMPⅡ,OMPⅡ,BMPⅡ,PMPⅡ）by modified the side chain of lysine residues in the sequence of MPⅡ,to improve biological activity.The analogs retain similar antibacterial activity to MPⅡ.The trypsin resistance of PMPⅡand BMPⅡwas significantly improved.Although the antibacterial activity of PMPⅡwas reduced by2-4 times,its trypsin resistance was increased by more than 1000 times higher compared with MPⅡ.The cytotoxicity of analogues toward mammalian red blood cells and normal cells is significantly reduced compared to the MPⅡ.In particular,PMPⅡexhibited extremely low hemolytic activity.MPⅡand its analogs are able to kill bacteria and fungi by destroying cell membranes.In addition,MPⅡand analogs can also exert antimicrobial activity by affecting the function of mitochondria in fungi.In summary,the minor-modification of the lysine side chain could effectively enhance the trypsin resistance of the analogs and greatly reduces the hemolytic activity of the MPⅡ,while retaining the antibacterial activity of MPⅡ.This study may provide new strategies to develop new antimicrobial agents and improve the clinical application of antimicrobial peptides.