Synthesis And Screening Of Oligoamidines And Their Antibacterial Applications

Antibiotic resistance is now a major global health threat.Synthetic antimicrobial peptidomimetics(AMPMs)have attracted much attention as a potentially powerful weapon against antibiotic resistance.However,AMPMs’membrane disruption mechanism which produced by electrostatic and hydrophobic interactions not only makes them resistance-resistant,but also enable them to non-specifically bind and destroy eukaryotic cell membranes as well.Therefore,eukaryotic toxicity issue due to the amphiphilic nature of AMPMs has been a major concern for their clinical applications.To find a feasible solution to the eukaryotic toxicity problem,the researchers have attempted to synthesize and screen diverse membrane-targeted antimicrobial agents,as well as to introduce additional antimicrobial mechanisms of action into the antimicrobial agents.Although some extent of membrane selectivity can be achieved through structural turning and screening,such toxicity problem is still the root problem of antimicrobial peptides and antimicrobial peptidomimetics that has put significant limitations in their clinical applications.Based on the structural characteristic of pentamidine that inhibits DNA synthesis by binding to small grooves in DNA through its amidine bonds,a series of oligomers derived from pentamidine analogs are designed and synthesized,which are named AMPMs.The optimal AMPM PT-b1 was obtained by screening for antimicrobial activity and biocompatibility of the AMPMs library.PT-b1 has additional prokaryotic targeting DNA-binding antimicrobial mechanism of action to aid its membrane-lysing behavior,so that the effective use concentration of this AMPM is reduced and it has decent antimicrobial potency without being too membrane-disruptive.To further improve the hemocompatibility of PT-b1,this project proposes a new strategy:amphiphilic masking strategy,i.e.,another FDA-approved,functional polymer,Pluronic F-127(PF127),can complex with an established AMPM to partially and reversibly“neutralize”its membrane disruptive ability for improved therapeutic index(TI).This strategy is extremely useful for AMPMs with multi-mechanistic,as it only weakens the membrane destruction mechanism by which cause eukaryotic toxicity,but does not inhibit other antimicrobial mechanisms of this AMPM.A PF127 solution containing PT-b1 can spontaneously form a temperaturesensitive,absorbable hydrogel at higher concentrations,but dissolve and complex with PT-b1 through hydrophobic interactions at lower concentrations or lower temperatures.And the complexation from PF127 can partially mask the amphiphilicity of PT-b1,making PT-b1 extremely hemocompatible.However,due to the reversibility in such nanocomplexation and the presence of multi-mechanistic of action of AMPM,the antibacterial efficacy of AMPM remains unchanged.By establishing a methicillin-resistant Staphylococcus aureus(MRSA)infected mouse epidermal wound model,demonstrating the in vivo effectiveness of this metal-free,multi-mechanistic antibacterial PF127-PT-b1 hydrogel system.The experimental results show that PF127-PT-b1 hydrogel is effective in promoting wound healing and inhibiting bacterial-induced inflammation even in the treatment involving drug-resistant pathogen infections.These findings present a promising solution for the eukaryotic toxicity issue that has been haunting the application of AMPMs.