A Frog-Derived Cathelicidin Peptide with Dual Antimicrobial and Immunomodulatory Activities Effectively Ameliorates Staphylococcus aureus-Induced Peritonitis in Mice

As antimicrobial resistance poses an increasing threat to public health, it is urgent to develop new antimicrobial agents. In this paper, we identify a novel 30-residue peptide (Nv-CATH, NCNFLCKVKQRLRSVSSTSHIGMAIPRPRG) from the skin of the frog Nanorana ventripunctata, which belongs to the cathelicidin family. Nv-CATH exhibited broad-spectrum antimicrobial activity against Gram-positive and Gram-negative bacteria. Nv-CATH significantly protected mice from lethal infections caused by Staphylococcus aureus. Furthermore, the peptide suppressed excessive and harmful inflammatory responses by repressing the production of NO, IL-6, TNF-α, and IL-1β. The NF-κB-NLRP3 and MAPK inflammatory signaling pathways were involved in the protection in vitro and in vivo. Nv-CATH also modulated macrophage/monocyte and neutrophil trafficking to the infection site by stimulating CXCL1, CXCL2, and CCL2 production in macrophages. Nv-CATH augmented immunocyte-mediated bacterial killing by modestly promoting neutrophils' phagocytosis and PMA-induced NET formation. Thus, Nv-CATH protects mice against bacterial infection by antimicrobial-immunomodulatory duality. The combination of these two characteristics makes Nv-CATH a promising molecule template for the development of novel antimicrobial and antibiotic-resistant agents.