TC-14, a cathelicidin-derived antimicrobial peptide with broad-spectrum antibacterial activity and high safety profile

Summary: Cathelicidins, a major class of antimicrobial peptides (AMPs), hold considerable potential for antimicrobial drug development. In the present study, we identified a novel cathelicidin AMP (TC-33) derived from the Chinese tree shrew. Despite TC-33 demonstrating weak antimicrobial activity, the novel peptide TC-14, developed based on its active region, exhibited a 432-fold increase in antimicrobial activity over the parent peptide. Structural analysis revealed that TC-14 adopted an amphipathic α-helical conformation. The bactericidal mechanism of TC-14 involved targeting and disrupting the bacterial membrane, leading to rapid membrane permeabilization and rupture. Furthermore, TC-14 exhibited a high-safety profile, as evidenced by the absence of cytotoxic and hemolytic activities, as well as high biocompatibility and safety in vivo. Of note, its potent antimicrobial activity provided significant protection in a murine model of skin infection. Overall, this study presents TC-14 as a promising drug candidate for antimicrobial drug development.