Citation: Zheng Xinyu, Cao Qiao, Cao Qin, Mao Fei, Li Xiaokang, Zhu Jin, Lan Lefu, Li Jian. Discovery of synergistic activity of fluoroquinolones in combination with antimicrobial peptides against clinical polymyxin-resistant Pseudomonas aeruginosa DK2[J]. Chinese Chemical Letters, ;2020, 31(2): 413-417. doi: 10.1016/j.cclet.2019.07.063 shu

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

Zheng Xinyu ^a ,
Cao Qiao ^b ,
Cao Qin ^b ,
Mao Fei ^a ,
Li Xiaokang ^a ,
Zhu Jin ^a,*, ,
Lan Lefu ^b,*, ,
Li Jian ^a,*,

a.
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
b.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

jinz@ecust.edu.cn

llan@simm.ac.cn

jianli@ecust.edu.cn

Received Date: 22 June 2019
Revised Date: 26 July 2019
Accepted Date: 30 July 2019
Available Online: 31 July 2019

Figures(2)

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 μg/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 from 512 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,
- Pseudomonas aeruginosa,
- Fluoroquinolones,
- Synergy,
- Cystic fibrosis,
- Antimicrobial peptides
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