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

1
Department of Chemistry, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
2
Institute of Animal Nutrition, Northeast Agricultural University, Harbin 150030, China
3
Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3A 1R9, Canada
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2018, 7(7), 158; https://doi.org/10.3390/jcm7070158
Received: 24 May 2018 / Revised: 12 June 2018 / Accepted: 19 June 2018 / Published: 22 June 2018
(This article belongs to the Special Issue Advances in Antibacterial Drug Discovery and Therapy)
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. View Full-Text
Keywords: tobramycin; efflux pump inhibitor; synergize; fluoroquinolones; rifampicin; fosfomycin; multidrug-resistant Pseudomonas aeruginosa tobramycin; efflux pump inhibitor; synergize; fluoroquinolones; rifampicin; fosfomycin; multidrug-resistant Pseudomonas aeruginosa
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MDPI and ACS Style

Yang, X.; Domalaon, R.; Lyu, Y.; Zhanel, G.G.; Schweizer, F. Tobramycin-Linked Efflux Pump Inhibitor Conjugates Synergize Fluoroquinolones, Rifampicin and Fosfomycin against Multidrug-Resistant Pseudomonas aeruginosa. J. Clin. Med. 2018, 7, 158.

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