Synthetic Mimics of Antimicrobial Peptides for the Targeted Therapy of Multidrug-Resistant Bacterial Infection.

Abstract

Antibacterial materials are highly demanded in treatment of bacterial infection, especially severe ones with multidrug-resistance. Herein, pH-responsive polypeptide, i.e., poly-L-lysine modified by 1-(propylthio)acetic acid-3-octylimidazolium and citraconic anhydride (PLL-POIM-CA), is synthesized by post-polymerization modification of poly-L-lysine (PLL) with 1-(propylthio)acetic acid-3-octylimidazolium (POIM) and citraconic anhydride (CA). It is observed that PLL-POIM-CA is stable under normal physiological condition, while CA cleaves rapidly at weakly acidic environment like bacterial infectious sites. The hydrolyzed PLL-POIM-CA exhibits excellent broad-spectrum antibacterial activities against Gram-negative bacteria of Escherichia coli and Gram-positive bacteria of Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA). In particular, the minimum inhibitory concentration (MIC) against multidrug-resistant bacteria like MRSA is as low as 7.8 µg mL^-1 . Moreover, PLL-POIM-CA exhibits good biocompatibility with mouse fibroblast cells (L929) in vitro and improved hemocompatibility with an HC₅₀ exceeding 5000 µg mL^-1 . Therefore, PLL-POIM-CA displays an excellent bacteria versus cells selectivity (HC₅₀ /MIC) over 534, which is 53 times higher than natural antimicrobial peptide of indolicidin. It is further demonstrated in vivo that the antimicrobial polypeptide effectively accelerates MRSA-infected wound healing by relieving local inflammatory response. Therefore, this targeted antimicrobial polypeptide has broad application prospects for the treatment of multidrug-resistant bacterial infection.