title: Adjuvants Based on Hybrid Antibiotics Overcome Resistance in Pseudomonas aeruginosa and Enhance Fluoroquinolone Efficacy.
abstract: The use of adjuvants that rescue antibiotics against multidrug-resistant (MDR) pathogens is a promising combination strategy for overcoming bacterial resistance. While the combination of β-lactam antibiotics and β-lactamase inhibitors has been successful in restoring antibacterial efficacy in MDR bacteria, the use of adjuvants to restore fluoroquinolone efficacy in MDR Gram-negative pathogens has been challenging. We describe tobramycin-ciprofloxacin hybrid adjuvants that rescue the activity of fluoroquinolone antibiotics against MDR and extremely drug-resistant Pseudomonas aeruginosa isolates in vitro and enhance fluoroquinolone efficacy in vivo. Structure-activity studies reveal that the presence of both tobramycin and ciprofloxacin, which are separated by a C12 tether, is critical for the function of the adjuvant. Mechanistic studies indicate that the antibacterial modes of ciprofloxacin are retained while the role of tobramycin is limited to destabilization of the outer membrane in the hybrid.
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: Goutam
authors.initials: G
authors.lastname: Guchhait
authors.affiliation: Department of Microbiology, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada).
authors.forename: Dinesh M
authors.initials: DM
authors.lastname: Fernando
authors.affiliation: Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada).
authors.forename: Soumya
authors.initials: S
authors.lastname: Deo
authors.affiliation: Department of Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada).|Department of Biochemistry and Medical Genetics, Winnipeg, MB, R3T 2N2 (Canada).
authors.forename: Sean A
authors.initials: SA
authors.lastname: McKenna
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 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 Chemistry, University of Manitoba, Winnipeg, MB, R3T 2N2 (Canada). Frank.Schweizer@umanitoba.ca.|Department of Medical Microbiology, University of Manitoba, Winnipeg, MB, R3T 1R9 (Canada). Frank.Schweizer@umanitoba.ca.
authors.forename: Frank
authors.initials: F
authors.lastname: Schweizer
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D024841:Fluoroquinolones / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D011550:Pseudomonas aeruginosa / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones
keywords: Pseudomonas aeruginosa; aminoglycosides; antibiotics; drug design; fluoroquinolones