jm7b00156_si_002.csv (1.5 kB)
A Tobramycin Vector Enhances Synergy and Efficacy of Efflux Pump Inhibitors against Multidrug-Resistant Gram-Negative Bacteria
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posted on 2017-04-11, 00:00 authored by Xuan Yang, Sudeep Goswami, Bala Kishan Gorityala, Ronald Domalaon, Yinfeng Lyu, Ayush Kumar, George G. Zhanel, Frank SchweizerDrug
efflux mechanisms interact synergistically with the outer
membrane permeability barrier of Gram-negative bacteria, leading to
intrinsic resistance that presents a major challenge for antibiotic
drug development. Efflux pump inhibitors (EPIs) which block the efflux
of antibiotics synergize antibiotics, but the clinical development
of EPI/antibiotic combination therapy to treat multidrug-resistant
(MDR) Gram-negative infections has been challenging. This is in part
caused by the inefficiency of current EPIs to penetrate the outer
membrane and resist efflux. We demonstrate that conjugation of a tobramycin
(TOB) vector to EPIs like NMP, paroxetine, or DBP enhances synergy
and efficacy of EPIs in combination with tetracycline antibiotics
against MDR Gram-negative bacteria including Pseudomonas aeruginosa. Besides potentiating tetracycline antibiotics, TOB–EPI conjugates
can also suppress resistance development to the tetracycline antibiotic
minocycline, thereby providing a strategy to develop more effective
adjuvants to rescue tetracycline antibiotics from resistance in MDR
Gram-negative bacteria.
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Gram-negative bacteriatetracycline antibiotic minocyclinemembrane permeability barrierEPITOBGram-negative infectionsresistance developmenttetracycline antibioticsMDREfflux Pump InhibitorsMultidrug-Resistant Gram-Negative Bacteria Drug efflux mechanismsantibiotics synergize antibioticsPseudomonas aeruginosapotentiating tetracycline antibioticsNMPTobramycin Vector Enhances Synergyantibiotic drug developmentrescue tetracycline antibioticsDBP
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