Polymyxin B₃–Tobramycin Hybrids with <i>Pseudomonas aeruginosa</i>-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 <i>Pseudomonas aeruginosa</i>. 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) <i>P. aeruginosa</i> clinical isolates. Furthermore, the most potent hybrid was able to synergize with currently used antibiotics against wild-type and MDR/XDR <i>P. aeruginosa</i> but also against <i>Acinetobacter baumannii</i> 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