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A Tobramycin Vector Enhances Synergy and Efficacy of Efflux Pump Inhibitors against Multidrug-Resistant Gram-Negative Bacteria

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posted on 11.04.2017, 00:00 by Xuan Yang, Sudeep Goswami, Bala Kishan Gorityala, Ronald Domalaon, Yinfeng Lyu, Ayush Kumar, George G. Zhanel, Frank Schweizer
Drug 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.