Guanidinylated Amphiphilic Tobramycin Derivatives Synergize with β-Lactam/β-Lactamase Inhibitor Combinations against Pseudomonas aeruginosa

Carbapenem-resistant Pseudomonas aeruginosa (P. aeruginosa) was designated as a critical priority pathogen by the World Health Organization for which new therapeutic solutions are required. With the rapid dissemination of β-lactamases in P. aeruginosa, β-lactam (BL) antibiotics are used in conjunction with β-lactamase inhibitors (BLI). The effectiveness of the BL/BLI combination could be further enhanced with the inclusion of an outer membrane (OM) permeabilizer, such as aminoglycosides and aminoglycoside-based adjuvants. Thus, the development of seven tobramycin derivatives reported herein focused on improving OM permeabilizing capabilities and reducing associated toxicity. The structure–activity relationship studies emphasized the effects of the nature of the cationic group; the number of polar head groups and positive charges; and flexibility, length, and steric bulk of the hydrophobic moiety. The optimized guanidinylated tobramycin-biphenyl derivative was noncytotoxic and demonstrated the ability to potentiate ceftazidime and aztreonam monotherapy and in dual combinations with avibactam against multidrug-resistant (MDR) and β-lactamase harboring isolates of P. aeruginosa. The triple combination of ceftazidime/avibactam plus guanidinylated tobramycin-biphenyl resulted in rapid bactericidal activity within 4–8 h of treatment, demonstrating the potential application of these guanidinylated amphiphilic tobramycin derivatives in augmenting BL/BLI combinations.