title: Hybrid Antibiotic Overcomes Resistance in P. aeruginosa by Enhancing Outer Membrane Penetration and Reducing Efflux.
abstract: Therapeutic interventions to treat multidrug-resistant (MDR) Pseudomonas aeruginosa infections are severely limited and often require the use of colistin as drug of last resort. The major challenges impeding the development of novel antipseudomonal agents are the lack of cell penetration and extensive efflux. We have discovered a tobramycin-moxifloxacin hybrid core structure which enhances outer membrane permeability and reduces efflux by dissipating the proton motive force of the cytoplasmic membrane in P. aeruginosa. The optimized hybrid protects Galleria mellonella larvae from the lethal effects of MDR P. aeruginosa. Attempts to select for resistance over a period of 25 days resulted in a 2-fold increase in the minimal inhibitory concentration (MIC) for the hybrid, while moxifloxacin or tobramycin resulted in a 16- and 512-fold increase in MIC. Although the hybrid possesses potent activity against MDR, P. aeruginosa isolates the activity that can be synergized when used in combination with other classes of antibiotics.
authors.affiliation: Department of Chemistry, University of Manitoba , 144 Dysart Road, 450 Parker Building, Winnipeg, Manitoba R3T 2N2, Canada.
authors.forename: Bala Kishan
authors.initials: BK
authors.lastname: Gorityala
authors.affiliation: Department of Chemistry, University of Manitoba , 144 Dysart Road, 450 Parker Building, Winnipeg, Manitoba R3T 2N2, Canada.
authors.forename: Goutam
authors.initials: G
authors.lastname: Guchhait
authors.affiliation: Department of Chemistry, University of Manitoba , 144 Dysart Road, 450 Parker Building, Winnipeg, Manitoba R3T 2N2, Canada.
authors.forename: Sudeep
authors.initials: S
authors.lastname: Goswami
authors.affiliation: Department of Microbiology, University of Manitoba , Winnipeg, Manitoba R3T 2N2, Canada.
authors.forename: Dinesh M
authors.initials: DM
authors.lastname: Fernando
authors.affiliation: Department of Microbiology, University of Manitoba , Winnipeg, Manitoba R3T 2N2, Canada.|Department of Medical Microbiology, University of Manitoba , Winnipeg, Manitoba R3T 1R9, Canada.
authors.forename: Ayush
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Medical Microbiology, University of Manitoba , Winnipeg, Manitoba R3T 1R9, Canada.
authors.forename: George G
authors.initials: GG
authors.lastname: Zhanel
authors.affiliation: Department of Chemistry, University of Manitoba , 144 Dysart Road, 450 Parker Building, Winnipeg, Manitoba R3T 2N2, Canada.|Department of Medical Microbiology, University of Manitoba , Winnipeg, Manitoba R3T 1R9, Canada.
authors.forename: Frank
authors.initials: F
authors.lastname: Schweizer
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D024841:Fluoroquinolones / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D000077266:Moxifloxacin; D011552:Pseudomonas Infections / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000166:cytology / Q000187:drug effects*; D014031:Tobramycin / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D000077266:Moxifloxacin; D014031:Tobramycin