Novel Tree Shrew-Derived\nAntimicrobial Peptide with\nBroad-Spectrum Antibacterial Activity

The number of cationic residues and net charge are critical\nfor\nthe activity of antimicrobial peptides (AMPs) due to their role in\nfacilitating initial electrostatic interactions with negatively charged\nbacterial membranes. A cathelicidin AMP (TC-33) has been identified\nfrom the Chinese tree shrew in our previous work, which exhibited\nweak antimicrobial activity, likely due to its moderately cationic\nnature. In the current study, based on TC-33, we designed a novel\nAMP by peptide truncation and Glu substitutions to increase its net\ncationic charge from +4 to +8. The resulting peptide, TC-LAR-18, showed\n4–128-fold enhanced antimicrobial activity relative to TC-33\nwithout causing hemolysis and cytotoxicity within 100 μg/mL.\nTC-LAR-18 effectively eliminated both planktonic and biofilm-associated\nbacteria, demonstrating rapid bactericidal effects due to its ability\nto quickly penetrate and disrupt bacterial cell membranes with a low\npropensity to induce resistance. Notably, TC-LAR-18 provided substantial\nprotection against skin bacterial infection in mice, underscoring\nits therapeutic potential. These findings not only highlight the importance\nof positively charged residues for the antibacterial activity of AMPs\nbut also present a useful drug candidate for combating multidrug-resistant\nbacteria.