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.

中文翻译：

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铜绿假单胞菌的多粘菌素B _{3 –}妥布霉素杂种-利福平，米诺环素和万古霉素的选择性抗菌活性和强增效作用

迫切需要开发能够根除铜绿假单胞菌等耐药革兰氏阴性病原体的新型抗菌剂。抗菌杂种已成为对抗细菌耐药性的一种有前途的策略，既可以作为独立药物使用，也可以作为佐剂与现有抗生素结合使用。在此，我们首次报道了由多粘菌素B ₃经由脂族烃接头与妥布霉素共价连接的多粘菌素B ₃组成的多粘菌素-氨基糖苷异二聚体的合成和生物学评估。多粘菌素B _3-妥布霉素杂种显示出对碳青霉烯耐药性以及对多种药物或广泛耐药性（MDR / XDR）的铜绿假单胞菌有效的活性临床分离株。此外，最有效的杂种能够与目前使用的针对野生型和MDR / XDR铜绿假单胞菌的抗生素协同作用，而且还针对鲍曼不动杆菌。本文所述的有前途的生物活性值得对能够克服抗药性问题的新型抗微生物杂种进行设计和开发的进一步研究。