文献类型：期刊文献

英文题名：Discovery of synergistic activity of fluoroquinolones in combination with antimicrobial peptides against clinical polymyxin-resistant Pseudomonas aeruginosa DK2

作者：Zheng, Xinyu[1];Cao, Qiao[2];Cao, Qin[2];Mao, Fei[1];Li, Xiaokang[1];Zhu, Jin[1];Lan, Lefu[2];Li, Jian[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

年份：2020

卷号：31

期号：2

起止页码：413

外文期刊名：CHINESE CHEMICAL LETTERS

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000510956700024)】；

基金：This work was supported by the National Key R&D Program of China (No. 2017YFB0202600), the National Natural Science Foundation of China (Nos. 21672064, 21702061, 81861138047), the Innovative Research Team of High-level Local Universities in Shanghai, the National Special Fund for State Key Laboratory of Bioreactor Engineering (No. 2060204), "Shu Guang" project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation (No. 14SG28) and the Shanghai Sailing Program (No. 17YF1403600).

语种：英文

外文关键词：Polymyxin B; Pseudomonas aeruginosa; Fluoroquinolones; Synergy; Cystic fibrosis; Antimicrobial peptides

摘要：Polymyxin B (PB), as the last-line of defense against multidrug-resistant Gram-negative bacteria, has caused resistance to P. aeruginosa recently. Fortunately, synergistic treatment could preserve the last class of antibiotics and reduce the emergency of drug resistance. Here, we performed a screen of 970 approved drugs synergized with PB against the P. aeruginosa DK2, which is severely resistant to PB, MIC = 512 mu g/mL. Encouragingly, we found fluoroquinolones could synergy with PB and achieved an obvious reduction in MIC of PB below the clinical susceptible breakpoint (2 mu g/mL). Especially, gemifloxacin achieved the highest synergistic effect with PB, leading to a 4096-fold MIC reduction (reduced from 512 mu g/mL to 0.125 mu g/mL). Furthermore, synergistic effect was also observed in the combination of gemifloxacin and colistin. Finally, outer membrane permeabilization assay showed that gemifloxacin could increase the permeability of bacterial cell membranes for P. aeruginosa which partly explained the synergy mechanism. These results indicate that fluoroquinolones represent attractive synergists to address the emerging threat of polymyxin-resistant infections. (C) 2019 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.