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

Abstract

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.