Improving the Antimicrobial Performance of Amphiphilic Cationic Antimicrobial Peptides Using Glutamic Acid Full-Scan and Positive Charge Compensation Strategies

Nonselective toxicity of antimicrobial peptides (AMPs) needs to be solved urgently for their application. Temporin-PE (T-PE, FLPIVAKLLSGLL-NH2), an AMP extracted from skin secretions of frogs, has high toxicity and specific antimicrobial activity against Gram-positive bacteria. To improve the antimicrobial performance of T-PE, a series of T-PE analogues were designed and synthesized by glutamic acid full-scan, and then their key positions were replaced with lysine. Finally, E11K4K10, the highest therapeutic indicial AMP, was screened out. E11K4K10 was not easy to induce and produce drug-resistant bacteria when used alone, as well as it could also inhibit the development of the drug resistance of traditional antibiotics when it was used in combination with the traditional antibiotics. In addition, E11K4K10 had an excellent therapeutic effect on a mouse model of pulmonary bacterial infection. Taken together, this study provides a new approach for the further improvement of new antimicrobial peptides against the antimicrobial-resistance crisis.

抗菌肽（antimicrobial peptides, AMPs）的非选择性毒性问题亟待解决，以推动其实际应用。Temporin-PE（T-PE，FLPIVAKLLSGLL-NH2）是从青蛙皮肤分泌物中提取的一类抗菌肽，对革兰氏阳性菌兼具高效抗菌活性与特异性杀伤作用。为优化T-PE的抗菌性能，研究团队通过谷氨酸全扫描策略设计并合成了一系列T-PE类似物，随后将其关键氨基酸位点替换为赖氨酸。最终筛选得到治疗指数最高的候选抗菌肽E11K4K10。该多肽单独使用时不易诱导产生耐药菌，与传统抗生素联用时还可抑制后者的耐药性发展。此外，E11K4K10对肺部细菌感染小鼠模型展现出优异的治疗效果。综上，本研究为应对抗菌耐药危机的新型抗菌肽的进一步优化提供了全新研究路径。