Polymyxin B3–Tobramycin Hybrids with Pseudomonas aeruginosa-Selective Antibacterial Activity and Strong Potentiation of Rifampicin, Minocycline, and Vancomycin

There is an urgent need to develop novel antibacterial agents able to eradicate drug-resistant Gram-negative pathogens such as Pseudomonas aeruginosa. Antimicrobial hybrids have emerged as a promising strategy to combat bacterial resistance, as a stand-alone drug but also as an adjuvant in combination with existing antibiotics. Herein, we report for the first time the synthesis and biological evaluation of polymyxin-aminoglycoside heterodimers composed of polymyxin B3 covalently linked to tobramycin via an aliphatic hydrocarbon linker. The polymyxin B3-tobramycin hybrids demonstrate potent activity against carbapenem-resistant as well as multidrug- or extensively drug-resistant (MDR/XDR) P. aeruginosa clinical isolates. Furthermore, the most potent hybrid was able to synergize with currently used antibiotics against wild-type and MDR/XDR P. aeruginosa but also against Acinetobacter baumannii as well. The promising biological activity described herein warrants additional studies into design and development of new antimicrobial hybrids able to surmount the problem of antimicrobial resistance.