title: A Tobramycin Vector Enhances Synergy and Efficacy of Efflux Pump Inhibitors against Multidrug-Resistant Gram-Negative Bacteria.
abstract: 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.
authors.affiliation: Department of Chemistry, University of Manitoba , Winnipeg, MB R3T 2N2, Canada.
authors.forename: Xuan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Chemistry, University of Manitoba , Winnipeg, MB R3T 2N2, Canada.
authors.forename: Sudeep
authors.initials: S
authors.lastname: Goswami
authors.affiliation: Department of Chemistry, University of Manitoba , Winnipeg, MB R3T 2N2, Canada.
authors.forename: Bala Kishan
authors.initials: BK
authors.lastname: Gorityala
authors.affiliation: Department of Chemistry, University of Manitoba , Winnipeg, MB R3T 2N2, Canada.
authors.forename: Ronald
authors.initials: R
authors.lastname: Domalaon
authors.affiliation: Department of Chemistry, University of Manitoba , Winnipeg, MB R3T 2N2, Canada.|Institute of Animal Nutrition, Northeast Agricultural University , Harbin, Heilongjiang 150030, P.R. China.
authors.forename: Yinfeng
authors.initials: Y
authors.lastname: Lyu
authors.affiliation: Department of Microbiology, University of Manitoba , Winnipeg, MB R3T 2N2, Canada.|Department of Medical Microbiology, University of Manitoba , Winnipeg, MB R3T 1R9, Canada.
authors.forename: Ayush
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Medical Microbiology, University of Manitoba , Winnipeg, MB R3T 1R9, Canada.
authors.forename: George G
authors.initials: GG
authors.lastname: Zhanel
authors.affiliation: Department of Chemistry, University of Manitoba , Winnipeg, MB R3T 2N2, Canada.|Department of Medical Microbiology, University of Manitoba , Winnipeg, MB R3T 1R9, Canada.
authors.forename: Frank
authors.identifier: 0000-0001-8697-5519
authors.initials: F
authors.lastname: Schweizer
mesh_terms: D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000378:metabolism*; D014031:Tobramycin / Q000494:pharmacology*
chemical_list: D026901:Membrane Transport Proteins; D014031:Tobramycin