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J Clin Med. 2018 Jun 22;7(7). pii: E158. doi: 10.3390/jcm7070158.

Tobramycin-Linked Efflux Pump Inhibitor Conjugates Synergize Fluoroquinolones, Rifampicin and Fosfomycin against Multidrug-Resistant Pseudomonas aeruginosa.

Author information

1
Department of Chemistry, University of Manitoba, Winnipeg, MB R3T 2N2, Canada. yangx315@myumanitoba.ca.
2
Department of Chemistry, University of Manitoba, Winnipeg, MB R3T 2N2, Canada. umdomala@myumanitoba.ca.
3
Department of Chemistry, University of Manitoba, Winnipeg, MB R3T 2N2, Canada. lvyinfeng2010@163.com.
4
Institute of Animal Nutrition, Northeast Agricultural University, Harbin 150030, China. lvyinfeng2010@163.com.
5
Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3A 1R9, Canada. ggzhanel@pcs.mb.ca.
6
Department of Chemistry, University of Manitoba, Winnipeg, MB R3T 2N2, Canada. Frank.Schweizer@umanitoba.ca.
7
Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3A 1R9, Canada. Frank.Schweizer@umanitoba.ca.

Abstract

In this study, we examined the in vitro effect of tobramycin-efflux pump inhibitor (TOB-EPI) conjugates in combinations with fluoroquinolones, rifampicin and fosfomycin on the growth of multi-drug resistant (MDR) and extremely-drug resistant (XDR) Pseudomonas aeruginosa. The TOB-EPI conjugates include tobramycin covalently linked to 1-(1-naphthylmethyl)-piperazine (NMP) (1), paroxetine (PAR) (2) and a dibasic peptide analogue of MC-04,124 (DBP) (3). Potent synergism was found for combinations of TOB-NMP (1), TOB-PAR (2) or TOB-DBP (3) with either fluoroquinolones (moxifloxacin, ciprofloxacin), rifampicin or fosfomycin against a panel of multidrug-resistant/extensively drug-resistant (MDR/XDR) P. aeruginosa clinical isolates. In the presence of ≤8 mg/L (6.1⁻7.2 µM) (≤¼ × MICadjuvant) concentration of the three conjugates, the MIC80 of moxifloxacin, ciprofloxacin, rifampicin and fosfomycin were dramatically reduced. Furthermore, the MIC80 of rifampicin (0.25⁻0.5 mg/L) and fosfomycin (8⁻16 mg/L) were reduced below their interpretative susceptibility breakpoints. Our data confirm the ability of TOB-NMP (1), TOB-PAR (2) and TOB-DBP (3) conjugates to strongly synergize with moxifloxacin, ciprofloxacin, rifampicin and fosfomycin against MDR/XDR P. aeruginosa. These synergistic combinations warrant further studies as there is an urgent need to develop new strategies to treat drug-resistant P. aeruginosa infections.

KEYWORDS:

efflux pump inhibitor; fluoroquinolones; fosfomycin; multidrug-resistant Pseudomonas aeruginosa; rifampicin; synergize; tobramycin

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