Potential of novel antimicrobial peptide P3 from bovine erythrocytes and its analogs to disrupt bacterial membranes in vitro and display activity against drug-resistant bacteria in a mouse model

• Published in: Antimicrobial agents and chemotherapy 2015-05, Vol.59 (5), p.2835-2841
• Main Authors: Zhang, Qinghua, Xu, Yanzhao, Wang, Qing, Hang, Bolin, Sun, Yawei, Wei, Xiaoxiao, Hu, Jianhe
• Format: Article
• Language: English
• Subjects: Animals; Anti-Infective Agents; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacology; Anti-Infective Agents - therapeutic use; Antimicrobial Cationic Peptides; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; Antimicrobial Cationic Peptides - therapeutic use; Bacteremia - drug therapy; Bacteremia - microbiology; Bacteria; Biosynthesis; Candida albicans - drug effects; Cattle; Cell Membrane Permeability - drug effects; Chemistry; Chemistry; Biosynthesis; Circular Dichroism; Drug Resistance, Multiple, Bacterial; Erythrocytes; Erythrocytes - chemistry; Escherichia coli - drug effects; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Staphylococcus aureus - drug effects
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.04932-14

With the emergence of many antibiotic-resistant strains worldwide, antimicrobial peptides (AMPs) are being evaluated as promising alternatives to conventional antibiotics. P3, a novel hemoglobin peptide derived from bovine erythrocytes, exhibited modest antimicrobial activity in vitro. We evaluated the antimicrobial activities of P3 and an analog, JH-3, both in vitro and in vivo. The MICs of P3 and JH-3 ranged from 3.125 μg/ml to 50 μg/ml when a wide spectrum of bacteria was tested, including multidrug-resistant strains. P3 killed bacteria within 30 min by disrupting the bacterial cytoplasmic membrane and disturbing the intracellular calcium balance. Circular dichroism (CD) spectrometry showed that P3 assumed an α-helical conformation in bacterial lipid membranes, which was indispensable for antimicrobial activity. Importantly, the 50% lethal dose (LD50) of JH-3 was 180 mg/kg of mouse body weight after intraperitoneal (i.p.) injection, and no death was observed at any dose up to 240 mg/kg body weight following subcutaneous (s.c.) injection. Furthermore, JH-3 significantly decreased the bacterial count and rescued infected mice in a model of mouse bacteremia. In conclusion, P3 and an analog exhibited potent antimicrobial activities and relatively low toxicities in a mouse model, indicating that they may be useful for treating infections caused by drug-resistant bacteria.