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

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^ε -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, PLL₂₂ -Gua is most effective against bacteria and yeast. Particularly, excellent bactericidal activity is observed against Staphylococcus aureus and MRSA. PLL₂₂ -Gua kills bacteria mainly by membrane translocation. In addition, PLL₂₂ -Gua kills MRSA with low resistance frequency (<3.3 × 10^-8 ). In an MRSA-caused wound infection mouse model, two-day treatment (twice daily) with 10, 20, or 40 mg per kg of PLL₂₂ -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 PLL₂₂ -Gua as an antimicrobial agent against multidrug-resistant infection in vivo.