Lyu Yinfeng, Domalaon Ronald, Yang Xuan, Schweizer Frank
Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada.
Institute of Animal Nutrition, Northeast Agricultural University, Harbin, Heilongjiang, 150030, P.R. China.
Biopolymers. 2017 Dec 4. doi: 10.1002/bip.23091.
Peptidomimetic modification is a common route of optimization for biologically active peptides. Previous studies in our group have shown that conjugation of amphiphilic tobramycin to other antibacterials enhance their latent outer membrane permeabilizing and efflux blocking activity toward Gram-negative pathogens including Pseudomonas aeruginosa. Herein, we describe the antimicrobial adjuvant properties of amphiphilic lysine ligated to tobramycin. The most potent amphiphilic lysine-tobramycin conjugate 3 potentiated the antibacterial efficacy of 8 clinically used antibiotics against wild type, multidrug- and extensively drug-resistant P. aeruginosa isolates from Canadian hospitals whereas amphiphilic lysine 4 did not. Antibiotics that are synergistic with conjugate 3 included moxifloxacin, ciprofloxacin, erythromycin, chloramphenicol, trimethoprim, novobiocin, linezolid, and fosfomycin. Out of these 8 antibiotics, novobiocin showed highest synergy.
拟肽修饰是生物活性肽优化的常见途径。我们小组之前的研究表明，两亲性妥布霉素与其他抗菌剂结合可增强其对包括铜绿假单胞菌在内的革兰氏阴性病原体的潜在外膜通透和外排阻断活性。在此，我们描述了连接到妥布霉素的两亲性赖氨酸的抗菌佐剂特性。最有效的两亲性赖氨酸 - 妥布霉素缀合物3增强了8种临床使用的抗生素对来自加拿大医院的野生型、多重耐药和广泛耐药铜绿假单胞菌分离株的抗菌效果，而两亲性赖氨酸4则没有。与缀合物3具有协同作用的抗生素包括莫西沙星、环丙沙星、红霉素、氯霉素、甲氧苄啶、新生霉素、利奈唑胺和磷霉素。在这8种抗生素中，新生霉素显示出最高的协同作用。
