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

作　　者：Xinyu Zheng Qiao Cao Qin Cao Fei Mao Xiaokang Li Jin Zhu Lefu Lan Jian Li 

机构地区：[1]State Key Laboratory of Bioreactor Engineering,Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China [2]State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China

出　　处：《Chinese Chemical Letters》2020年第2期413-417,共5页中国化学快报（英文版）

基　　金：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);the Shanghai Sailing Program(No.17YF1403600)。

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=512μg/mL.Encouragingly,we found fluoroquinolones could synergy with PB and achieved an obvious reduction in MIC of PB below the clinical susceptible breakpoint(2 μg/mL).Especially,gemifloxacin achieved the highest synergistic effect with PB,leading to a 4096-fold MIC reduction(reduced from512 μg/mL to 0.125 μg/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.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=512μg/mL.Encouragingly,we found fluoroquinolones could synergy with PB and achieved an obvious reduction in MIC of PB below the clinical susceptible breakpoint(2 μg/mL).Especially,gemifloxacin achieved the highest synergistic effect with PB,leading to a 4096-fold MIC reduction(reduced from512 μg/mL to 0.125 μg/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.

关 键 词：POLYMYXIN B PSEUDOMONAS AERUGINOSA FLUOROQUINOLONES Synergy CYSTIC FIBROSIS Antimicrobial peptides 

分 类 号：R969[医药卫生—药理学]