Journal
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Volume 1864, Issue 4, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbagen.2020.129532
Keywords
Antimicrobial peptide; Hybridization; KFA3; Substance P; Cell selectivity; Immunomodulation
Categories
Funding
- National Natural Science Foundation of China (NSFC) [81874315, 81302798, 21432003]
- Program for Chang-jiang Scholars and Innovative Research Team in University (PCSIRT) [IRT_15R27]
- Fundamental Research Funds for the Central Universities [lzujbky-2018-k9, lzujbky-2018-87]
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Background: Hybridization is a useful strategy to bond the advantages of different peptides into novel constructions. We designed a series of AMPs based on the structures of a synthetic AMP KFA3 and a naturally-occurred host defense peptide substance P (SP) to obtain peptides retaining the high antibacterial activity of KFA3 and the immunomodulatory activity and low cytotoxicity of SP. Methods: Two repeats of KFA and different C terminal fragments of SP were hybridized, generating a series of novel AMPs (KFSP1-8). The antibacterial activities, host cell toxicity and immunomodulation were measured. The antibacterial mechanisms were investigated. Results: Hybrid peptides KFSP1-4 exerted substantial antibacterial activities against Gram-negative bacteria of standard strains and clinical drug-resistant isolates including E.coli, A.baumannii and P.aeruginosa, while showing little toxicity towards host cells. Compared with KFA3, moderate reduction in alpha-helix content and the interruption in a-helix continuality were indicated in CD spectra analysis and secondary-structure simulation in these peptides. Membrane permeabilization combined with time-kill studies and FITC-labeled imaging, indicated a selective membrane interaction of KFSP1 with bacteria cell membranes. By specially activating NK1 receptor, the hybrid peptides kept the ability of SP to induce intracellular calcium release and ERK1/2 phosphorylation, but unable to stimulate NF-kappa B phosphorylation. KFSP1 facilitated the survival of mouse macrophage RAW264.7, directly interacting with LPS and inhibiting the LPS-induced NF-kappa B phosphorylation and TNF-alpha expression. Conclusion: Hybridization is a useful strategy to bond the advantages of different peptides. KFSP1 and its analogs are worth of advanced efforts to explore their potential applications as novel antimicrobial agents.
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