Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, China; School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
Eur J Med Chem. 2021 Feb 15;212:113138. doi: 10.1016/j.ejmech.2020.113138. Epub 2020 Dec 29.
Facing the continuously urgent demands for novel antimicrobial agents since the growing emergence of bacterial resistance, a series of new ultra-short lipopeptides, composed of tryptophan and arginine and fatty acids, were de novo designed and synthesized in this study. Most of the new lipopeptides exhibited preferable antimicrobial potential against gram-positive bacteria, including MRSA clinical isolates. Among them, the new lipopeptides C14-R1 (C14-RWW-NH) and C12-R2 (C12-RRW-NH) presented higher selectivity to bacterial membranes over mammalian membranes and low cytotoxicity, which also maintained better antimicrobial activity in the presence of physiological salts or serum. Most importantly, C14-R1 and C12-R2 not only expressed low tendency of bacterial resistance, but also displayed synergistic antimicrobial activity against antibiotics-resistant bacteria when be used in combination with antibiotics. Especially, they could alleviate or reverse the ciprofloxacin resistance, implying an ideal anti-resistance function. Moreover, the new lipopeptides showed rapid killing kinetics, obvious effectiveness for persistent cells that escaped from antibiotics, and strong anti-biofilm ability, which further indicated a preferable anti-resistance ability. The typical non-receptor-mediated membrane mechanisms were characterized by LPS/LTA competitive inhibition, cytoplasmic membrane depolarization, PI uptake assay and scanning electron microscopy analyses systematically. Reactive oxygen species (ROS) generation assays supplemented their intracellular targets in the meanwhile. In addition to the remarkable antimicrobial activity in vivo, the new lipopeptides also displayed significant anti-inflammatory effect in vivo. To sum up, the new lipopeptides C14-R1 and C12-R2 viewed as novel antimicrobial alternatives for tackling the impending crisis of antimicrobial resistance.
面对细菌耐药性不断加剧所带来的对新型抗菌药物的迫切需求，本研究从头设计并合成了一系列由色氨酸和精氨酸与脂肪酸组成的新型超短脂肽。大多数新型脂肽对革兰氏阳性菌，包括耐甲氧西林金黄色葡萄球菌临床分离株，表现出较好的抗菌潜力。其中，新型脂肽 C14-R1（C14-RWW-NH）和 C12-R2（C12-RRW-NH）对细菌膜具有更高的选择性，对哺乳动物膜的选择性较低，细胞毒性低，在存在生理盐或血清的情况下仍能保持较好的抗菌活性。最重要的是，C14-R1 和 C12-R2 不仅表现出较低的细菌耐药倾向，而且在与抗生素联合使用时对抗生素耐药菌表现出协同抗菌活性。特别是，它们可以减轻或逆转环丙沙星的耐药性，暗示其具有理想的抗耐药功能。此外，新型脂肽还表现出快速的杀菌动力学，对逃避抗生素的持久性细胞具有明显的效果，以及较强的抗生物膜能力，这进一步表明其具有较好的抗耐药能力。典型的非受体介导的膜机制通过 LPS/LTA 竞争抑制、细胞质膜去极化、PI 摄取试验和扫描电子显微镜分析系统得到了系统表征。活性氧（ROS）生成试验同时补充了它们的细胞内靶标。除了在体内表现出显著的抗菌活性外，新型脂肽在体内还表现出显著的抗炎作用。总之，新型脂肽 C14-R1 和 C12-R2 被视为应对抗菌药物耐药性迫在眉睫危机的新型抗菌替代物。
