摘要
临床上常用的广谱抗生素无法有效解决抗生素高度耐药ESKAPE菌感染的难题,ESKAPE耐药菌已经成为人类生命健康的重大威胁.抗生素与佐剂的联合治疗是解决抗生素耐药菌感染的重要途径,但是探索对所有ESKAPE耐药菌都具有广谱和高效抗菌活性的抗生素-佐剂组合仍然面临巨大挑战.在这里,我们提出了一种抗生素-佐剂的有效设计策略,将对ESKAPE中耐药阴性菌具有高活性的多粘菌素B(PMB)与模拟宿主防御肽的细菌膜靶向阳离子聚(2-噁唑啉)相结合.我们通过2-噁唑啉单体可控聚合,合成了一系列具有不同疏水性侧链的阳离子聚(2-噁唑啉).研究表明,聚(2-噁唑啉)和PMB的组合效果随着聚(2-噁唑啉)侧链疏水性的提高呈现出从拮抗效应到协同效应的逐渐变化.其中,优选的聚(2-噁唑啉)EACA-POX_(20)显著增强了PMB的抗菌活性,尤其是对于ESKAPE耐药阳性菌的抗菌活性增强了16–32倍.聚(2-噁唑啉)EACA-POX_(20)有效增强了PMB的抗菌活性并扩展了PMB的抗菌谱.聚(2-噁唑啉)和PMB的组合策略能够有效对抗所有耐药ESKAPE病原体,为解决ESKAPE耐药菌提供了新的思路.
Antibiotic-resistant ESKAPE bacteria have become a significant threat to human health due to the ineffectiveness of clinically used broad-spectrum antibiotics.Combination therapy of antibiotic and adjuvant has emerged as a promising strategy to overcome antibiotic-resistant bacteria. However, the antibiotic-adjuvant combination with potent and broad-spectrum antimicrobial activities against all ESKAPE bacteria remains a huge challenge. Herein, we proposed an effective combination strategy of using polymyxin B(PMB) as the antibiotic, which exhibited potent activity against Gram-negative ESKAPE bacteria, and host defense peptide(HDP)-mimicking cationic antimicrobial poly(2-oxazoline)s that target bacterial membrane as the adjuvant. A series of cationic poly(2-oxazoline)s with varying hydrophobic side chain lengths were synthesized via the controllable2-oxazoline polymerization. The results indicate that the combination effect of PMB and HDP-mimicking poly(2-oxazoline)s exhibits the gradual change from antagonistic effect to synergistic effect as the hydrophobicity and ability to disrupt bacterial membrane of poly(2-oxazoline)s increase.Moreover, the optimal poly(2-oxazoline) EACA-POX_(20)significantly enhances the antibacterial activity of PMB, especially against Gram-positive ESKAPE bacteria with 16±32folds enhancement. The combination strategy of EACA-POX_(20)and PMB effectively broadens the antibacterial spectrum of PMB, enabling it to combat all drug-resistant ESKAPE bacteria. This study presents a promising approach for combating ESKAPE bacteria.
作者
罗政杰
赵学斌
周敏
邹景橙
肖希勉
刘龙强
谢佳洋
武月铭
张雯静
刘润辉
Zhengjie Luo;Xuebin Zhao;Min Zhou;Jingcheng Zou;Ximian Xiao;Longqiang Liu;Jiayang Xie;Yueming Wu;Wenjing Zhang;Runhui Liu(State Key Laboratory of Bioreactor Engineering,East China University of Science and Technology,Shanghai 200237,China;Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism,Key Laboratory for Ultrafine Materials of Ministry of Education,Frontiers Science Center for Materiobiology and Dynamic Chemistry,Research Center for Biomedical Materials of Ministry of Education,School of Materials Science and Engineering,East China University of Science and Technology,Shanghai 200237,China;Department of Orthopedic Surgery,Shanghai General Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai 200080,China)
基金
supported by the National Key Research and Development Program of China (2022YFC2303100)
the National Natural Science Foundation of China (T2325010, 22305082, 52203162, and 22075078)
Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism (Shanghai Municipal Education Commission)
the Program of Shanghai Academic/Technology Research Leader (20XD1421400)
the Open Research Fund of the State Key Laboratory of Polymer Physics and Chemistry (Changchun Institute of Applied Chemistry, Chinese Academy of Sciences)
the Open Project of Engineering Research Center of Dairy Quality and Safety Control Technology (Ministry of Education, R202201)
China National Postdoctoral Program for Innovative Talents (BX2021102)
China Postdoctoral Science Foundation (2022M710050)
the support of the Analysis and Testing Center of School of Chemical Engineering, East China university of Science and Technology。
