Antimicrobial Polypeptides Capable of Membrane Translocation for Treatment of MRSA Wound Infection In Vivo

• Published in: Advanced healthcare materials Vol. 11; no. 6; p. e2101770
• Main Authors: Yang, Shengcai, Wang, Yanming, Tan, Jason, Teo, Jye Yng, Tan, Ko Hui, Yang, Yi Yan
• Format: Journal Article
• Language: English
• Published: Germany 01.03.2022
• Subjects: antimicrobial; wound infection; membrane translocation; Guanidium-functionalized polypeptides; MRSA
• ISSN: 2192-2659
• DOI: 10.1002/adhm.202101770

Multidrug resistant infections are plaguing the healthcare sector over the past few decades with limited treatment options. To overcome this problem, the authors synthesize a series of novel guanidinium-functionalized polypeptides. Specifically, poly(l-lysine) (PLL) with different lengths is first synthesized by ring-opening polymerization of N -benzyloxycarbonyl-l-lysine-N-carboxyanhydride (Lys(Z)-NCA) followed by functionalization with a guanidinium-functional group to obtain guanidinium-functionalized PLL (PLL-Gua). To study the effect of hydrophobicity on antimicrobial activity, relatively more hydrophobic leucine-NCA monomer or hydrophobic vitamin E moiety is introduced to PLL-Gua. These polypeptides are characterized for antimicrobial activity against a panel of microbes including multidrug-resistant bacteria, and hemolytic activity. Among all the polypeptides, PLL -Gua is most effective against bacteria and yeast. Particularly, excellent bactericidal activity is observed against Staphylococcus aureus and MRSA. PLL -Gua kills bacteria mainly by membrane translocation. In addition, PLL -Gua kills MRSA with low resistance frequency (<3.3 × 10 ). In an MRSA-caused wound infection mouse model, two-day treatment (twice daily) with 10, 20, or 40 mg per kg of PLL -Gua shows up to 99.5% bacterial removal. Moreover, no acute dermal toxicity is observed even at a dose of 200 mg per kg. These promising results show the excellent potential of PLL -Gua as an antimicrobial agent against multidrug-resistant infection in vivo.