Biguanide-functionalized peptide mimics effectively combat drug-resistant ESKAPE pathogens and meningitis

ESKAPE pathogens-induced meningitis seriously threatens human health due to antimicrobial resistance and low permeability of blood-brain barrier (BBB). It's a promising strategy to combat drug-resistant pathogens using synthetic mimics of host defense peptide (HDP) bearing positive charges that are mainly provided by amine or guanidine. Here, we report that biguanide serves as a type of positively charged moiety to design HDP mimics. Biguanide exerts a stronger interaction with bacterial membrane phospholipids via bidentate hydrogen bonds than do amine and guanidine. The biguanide-functionalized HDP mimic, PBGProOx₂₀, targets bacterial membrane phospholipids to show potent activity against all ESKAPE pathogens and does not induce antimicrobial resistance. PBGProOx₂₀ exhibits promising BBB-penetrating property and displays potent therapeutic effects in female mice full-thickness infection model, sub-cutaneous infection model, kidney infection model, peritonitis model, and meningitis model. This study provides a promising strategy for designing HDP mimics to combat ESKAPE pathogens and meningitis.