An active domain HF-18 derived from hagfish intestinal peptide effectively inhibited drug-resistant bacteria in vitro/vivo

Antibiotic resistance is spreading faster than the development of new antibiotics into clinical practice. Currently, the design of antimicrobial peptides (AMPs), potential new antibacterial agents with rare antimicrobial resistance, is the available strategy to enhance the antimicrobial activity and lower the toxicity of AMPs. In this study, a peptide derived from hagfish intestinal peptide was designed and termed as HF-18 (GFFKKAWRKVKKAFRRVL). After antimicrobial/bactericidal test in vitro, we found that HF-18 exhibited a potent antimicrobial activity with MIC of only 4 μg/ml against drug-resistant Staphylococcus aureus (S. aureus). Meanwhile, it eliminated the test bacteria within 1 h, suggesting its rapid bactericidal effect. Importantly, this peptide had no obvious hemolytic activity and cytotoxicity to mammalian cells. Furthermore, its notable antimicrobial effects in vivo was confirmed again in S. aureus induced mouse bacteremia and skin wound infection, reflecting as the decrease in bacterial counts in mouse lung or skin (up to 1.9 or 3.5 log CFU respectively), and including the inhibitory activity on inflammatory cytokines secretion. The possible mechanisms underlying HF-18 against drug-resistant S. aureus may attribute that HF-18 neutralized the negative charge in S. aureus surface and then disrupted the integrity of cell membranes to enhance the permeation of bacterial membrane, showing as the increased uptake of NPN and PI and the obvious morphology changes of S. aureus. In addition, this peptide bound to bacterial genomic DNA to suppress the expression of Panton-Valentine leukocidin (pvl) and nuclease (nuc) genes, which play major roles in S. aureus virulence. The properties of HF-18 suggest a path towards developing antibacterial agents that has stronger antibacterial activity and greater security for clinical treatment of infection induced by S. aureus, especially drug-resistant S. aureus.