Guanidinylated Amphiphilic Tobramycin Derivates and B-Lactam/B-Lactamase Inhibitor Combinations for Treatment of Pseudomonas Aeruginosa Infections

Abstract

The effectiveness of β-lactam antibiotics when used in conjunction with a β-lactamase inhibitor to treat Pseudomonas aeruginosa infections is enhanced with the inclusion of an outer membrane permeabilizing tobramycin derivative. The optimized guanidinylated tobramycin-biphenyl derivatives are non-cytotoxic and demonstrated the ability to potentiate ceftazidime and aztreonam monotherapy and in dual combinations with avibactam against multidrug-resistant and f-lactamase harboring isolates of P. aeruginosa. The triple combination of ceftazidime/avibactam plus guanidinylated tobramycin-biphenyl resulted in a rapid bactericidal activity within 4-8 hours of treatment, demonstrating the potential application of these guanidinylated amphiphilic tobramycin derivatives in augmenting BL/BLI.

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