A Novel β-Hairpin Peptide Z-d14CFR Enhances Multidrug-Resistant Bacterial Clearance in a Murine Model of Mastitis

• Published in: International journal of molecular sciences Vol. 23; no. 9; p. 4617
• Main Authors: Wang, Xue, Li, Shuxian, Du, Mengze, Liu, Ning, Shan, Qiang, Zou, Yunjing, Wang, Jiufeng, Zhu, Yaohong
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 21-04-2022; MDPI
• Subjects: Animal models; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Anti-Infective Agents - pharmacology; Antibacterial activity; Antibiotics; Antimicrobial activity; Antimicrobial agents; antimicrobial peptide; Antimicrobial Peptides; Antimicrobial resistance; Bacteria; Bacterial infections; Biofilms; Chemical bonds; Clearances; Cytotoxicity; defensin; Defensins - pharmacology; Disease Models, Animal; Drug resistance; E coli; Escherichia coli; Female; Gram-negative bacteria; Gram-positive bacteria; Humans; IL-1β; Interleukin 1; Leukocytes (neutrophilic); Mass spectrometry; Mastitis; Mastitis - drug therapy; Metastases; Mice; Microbial Sensitivity Tests; Multidrug resistance; Multidrug resistant organisms; multidrug-resistant bacteria; Pathogens; Peptides; Peptides - pharmacology; Scientific imaging; Tumor necrosis factor-α; Zophobas atratus; β-hairpin; multidrug-resistant bacteria; Zophobas atratus; β-hairpin; mastitis; antimicrobial peptide; defensin
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23094617

The widespread prevalence of antimicrobial resistance has spawned the development of novel antimicrobial agents. Antimicrobial peptides (AMPs) have gained comprehensive attention as one of the major alternatives to antibiotics. However, low antibacterial activity and high-cost production have limited the applications of natural AMPs. In this study, we successfully expressed recombinant
(
) defensin for the first time. In order to increase the antimicrobial activity of peptide, we designed 5 analogues derived from
defensin, Z-d13, Z-d14C, Z-d14CF, Z-d14CR and Z-d14CFR. Our results showed that Z-d14CFR (RGCRCNSKSFCVCR-NH
) exhibited a broad-spectrum antimicrobial activity to both Gram-positive bacteria and Gram-negative bacteria, including multidrug-resistant bacteria. It possessed less than 5% hemolysis and 10% cytotoxicity, even at a high concentration of 1 mg/mL. Antimicrobial mechanism studies indicated that Z-d14CFR performed antimicrobial effect via inhibiting biofilm formation, disrupting bacterial membrane integrity and inducing cellular contents release. Furthermore, Z-d14CFR showed a great therapeutic effect on the treatment of multidrug-resistant
(
) infection by enhancing bacterial clearance, decreasing neutrophils infiltration and the expression of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) in a murine model of mastitis. Our findings suggest that Z-d14CFR could be a promising candidate against multidrug-resistant bacteria.