Luo Lin, Cai Ying, Su Yunhan, Li Chenxi, Tian Gengzhou, Wang Xingyu, Wu Zhongxiang, Chen Wenlin, Zhang Tianyu, Zhang Zhiye
Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650031, Yunnan, China.
Third Department of Breast Surgery, Peking University Cancer Hospital Yunnan, Third Affiliated Hospital of Kunming Medical University (Yunnan Cancer Hospital), Kunming 650118, Yunnan, China.
ACS Omega. 2024 Oct 30;9(45):45279-45288. doi: 10.1021/acsomega.4c06857. eCollection 2024 Nov 12.
The number of cationic residues and net charge are critical for the activity of antimicrobial peptides (AMPs) due to their role in facilitating initial electrostatic interactions with negatively charged bacterial membranes. A cathelicidin AMP (TC-33) has been identified from the Chinese tree shrew in our previous work, which exhibited weak antimicrobial activity, likely due to its moderately cationic nature. In the current study, based on TC-33, we designed a novel AMP by peptide truncation and Glu substitutions to increase its net cationic charge from +4 to +8. The resulting peptide, TC-LAR-18, showed 4-128-fold enhanced antimicrobial activity relative to TC-33 without causing hemolysis and cytotoxicity within 100 μg/mL. TC-LAR-18 effectively eliminated both planktonic and biofilm-associated bacteria, demonstrating rapid bactericidal effects due to its ability to quickly penetrate and disrupt bacterial cell membranes with a low propensity to induce resistance. Notably, TC-LAR-18 provided substantial protection against skin bacterial infection in mice, underscoring its therapeutic potential. These findings not only highlight the importance of positively charged residues for the antibacterial activity of AMPs but also present a useful drug candidate for combating multidrug-resistant bacteria.
阳离子残基的数量和净电荷对抗菌肽（AMPs）的活性至关重要，因为它们在促进与带负电荷的细菌膜的初始静电相互作用中发挥作用。在我们之前的工作中，从中国树鼩中鉴定出一种cathelicidin抗菌肽（TC-33），其抗菌活性较弱，可能是由于其适度的阳离子性质。在本研究中，基于TC-33，我们通过肽截短和谷氨酸取代设计了一种新型抗菌肽，将其净阳离子电荷从+4增加到+8。所得肽TC-LAR-18相对于TC-33显示出4至128倍增强的抗菌活性，且在100μg/mL浓度下不会引起溶血和细胞毒性。TC-LAR-18有效消除了浮游细菌和生物膜相关细菌，由于其能够快速穿透并破坏细菌细胞膜且诱导耐药性的倾向较低，显示出快速杀菌作用。值得注意的是，TC-LAR-18为小鼠皮肤细菌感染提供了显著保护，突出了其治疗潜力。这些发现不仅强调了带正电荷残基对抗菌肽抗菌活性的重要性，还提出了一种对抗多重耐药细菌的有用候选药物。
