Amphiphilic Tobramycin-Lysine Conjugates Sensitize Multidrug Resistant Gram-Negative Bacteria to Rifampicin and Minocycline.

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  • Additional Information
    • Source:
      Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
    • Publication Information:
      Publication: Washington Dc : American Chemical Society
      Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
    • Subject Terms:
      Anti-Bacterial Agents/*pharmacology ; Drug Resistance, Multiple, Bacterial/*drug effects ; Lysine/*chemistry ; Minocycline/*pharmacology ; Rifampin/*pharmacology ; Tobramycin/*pharmacology; Anti-Bacterial Agents/chemistry ; Gram-Negative Bacteria/drug effects ; Gram-Positive Bacteria/drug effects ; Hemolysis/drug effects ; Microbial Sensitivity Tests ; Models, Biological ; Tobramycin/chemistry
    • Abstract:
      Chromosomally encoded low membrane permeability and highly efficient efflux systems are major mechanisms by which Pseudomonas aeruginosa evades antibiotic actions. Our previous reports have shown that amphiphilic tobramycin-fluoroquinolone hybrids can enhance efficacy of fluoroquinolone antibiotics against multidrug-resistant (MDR) P. aeruginosa isolates. Herein, we report on a novel class of tobramycin-lysine conjugates containing an optimized amphiphilic tobramycin-C12 tether that sensitize Gram-negative bacteria to legacy antibiotics. Combination studies indicate the ability of these conjugates to synergize rifampicin and minocycline against MDR and extensively drug resistant (XDR) P. aeruginosa isolates and enhance efficacy of both antibiotics in the Galleria mellonella larvae in vivo infection model. Mode of action studies indicate that the amphiphilic tobramycin-lysine adjuvants enhance outer membrane cell penetration and affect the proton motive force, which energizes efflux pumps. Overall, this study provides a strategy for generating effective antibiotic adjuvants that overcome resistance of rifampicin and minocycline in MDR and XDR Gram-negative bacteria including P. aeruginosa.
    • Grant Information:
      MOP-119335 Canada CIHR
    • Accession Number:
      0 (Anti-Bacterial Agents)
      FYY3R43WGO (Minocycline)
      K3Z4F929H6 (Lysine)
      VJT6J7R4TR (Rifampin)
      VZ8RRZ51VK (Tobramycin)
    • Publication Date:
      Date Created: 20170415 Date Completed: 20170711 Latest Revision: 20181222
    • Publication Date:
      20231215
    • Accession Number:
      10.1021/acs.jmedchem.6b01742
    • Accession Number:
      28409644