Ramirez Danzel Marie, Dhiman Shiv, Mukherjee Ayan, Wimalasekara Ruwani, Schweizer Frank
Department of Chemistry, University of Manitoba Winnipeg MB R3T 2N2 Canada
Department of Microbiology, University of Manitoba Winnipeg MB R3T 2N2 Canada.
RSC Med Chem. 2024 Feb 16;15(3):1055-1065. doi: 10.1039/d3md00602f. eCollection 2024 Mar 20.
The emergence of aminoglycoside resistance has prompted the development of amphiphilic aminoglycoside derivatives which target bacterial membranes. Tobramycin and nebramine ether derivatives initially designed for this purpose were optimized and screened for their potential application as outer membrane (OM) permeabilizing adjuvants. Structure-activity relationship (SAR) studies revealed that the tobramycin benzyl ether was the most optimal OM permeabilizer, capable of potentiating rifampicin, novobiocin, vancomycin, minocycline, and doxycycline against Gram-negative bacteria. The innovative use of this compound as an adjuvant is highlighted by its ability to sensitize multidrug-resistant (MDR) Gram-negative bacteria to rifampicin and restore the susceptibility of MDR to minocycline.
氨基糖苷类耐药性的出现促使了针对细菌膜的两亲性氨基糖苷衍生物的开发。最初为此目的设计的妥布霉素和奈替米星醚衍生物经过优化，并筛选了它们作为外膜（OM）通透佐剂的潜在应用。构效关系（SAR）研究表明，妥布霉素苄基醚是最理想的OM通透剂，能够增强利福平、新生霉素、万古霉素、米诺环素和强力霉素对革兰氏阴性菌的作用。该化合物作为佐剂的创新用途体现在它能够使多重耐药（MDR）革兰氏阴性菌对利福平敏感，并恢复MDR对米诺环素的敏感性。
