Dhiman Shiv, Ramirez Danyel, Li Yanqi, Kumar Ayush, Arthur Gilbert, Schweizer Frank
Department of Chemistry, University of Manitoba, Winnipeg R3T 2N2, Manitoba, Canada.
Department of Microbiology, University of Manitoba, Winnipeg R3T 2N2, Manitoba, Canada.
ACS Infect Dis. 2023 Apr 14;9(4):864-885. doi: 10.1021/acsinfecdis.2c00549. Epub 2023 Mar 14.
According to the World Health Organization, antibiotic resistance is a global health threat. Of particular importance are infections caused by multidrug-resistant Gram-negative bacteria including , , , and for which limited treatment options exist. Multiple and simultaneously occurring resistance mechanisms including outer membrane impermeability, overexpression of efflux pumps, antibiotic-modifying enzymes, and modification of genes and antibiotic targets have made antibiotic drug development more difficult against these pathogens. One strategy to cope with these challenges is the use of outer membrane permeabilizers that increase the intracellular concentration of antibiotics when used in combination. In some circumstances, this approach can rescue antibiotics from resistance or repurpose currently marketed antibiotics. Tobramycin-based hybrid antibiotic adjuvants that combine two outer membrane-active components have been previously shown to potentiate antibiotics by facilitating transit through the outer membrane, resulting in increased antibiotic accumulation within the cell. Herein, we extended the concept of tobramycin-based hybrid antibiotic adjuvants to tobramycin-based chimeras by engineering up to three different membrane-active antibiotic warheads such as tobramycin, 1-(1-naphthylmethyl)-piperazine, ciprofloxacin, and cyclam into a central 1,3,5-triazine scaffold. Chimera (TOB-TOB-CIP) consistently synergized with ciprofloxacin, levofloxacin, and moxifloxacin against wild-type and fluoroquinolone-resistant . Moreover, the susceptibility breakpoints of ceftazidime, aztreonam, and imipenem were reached using the triple combination of chimera with ceftazidime/avibactam, aztreonam/avibactam, and imipenem/relebactam, respectively, against β-lactamase-harboring . Our findings demonstrate that tobramycin-based chimeras form a novel class of antibiotic potentiators capable of restoring the activity of antibiotics against .
根据世界卫生组织的说法，抗生素耐药性是对全球健康的一种威胁。特别重要的是由多重耐药革兰氏阴性菌引起的感染，包括 、 、 和 ，针对这些感染的治疗选择有限。多种同时出现的耐药机制，包括外膜通透性、外排泵过度表达、抗生素修饰酶以及基因和抗生素靶点的修饰，使得针对这些病原体的抗生素药物研发更加困难。应对这些挑战的一种策略是使用外膜通透剂，当与抗生素联合使用时，可增加抗生素在细胞内的浓度。在某些情况下，这种方法可以使抗生素从耐药状态中恢复活性，或者重新利用目前已上市的抗生素。之前已经证明，结合了两种外膜活性成分的基于妥布霉素的混合抗生素佐剂通过促进抗生素穿过外膜来增强抗生素的作用，从而导致细胞内抗生素积累增加。在此，我们通过将多达三种不同的膜活性抗生素弹头，如妥布霉素、1-(1-萘甲基)-哌嗪、环丙沙星和环拉胺，设计到一个中心1,3,5-三嗪支架中，将基于妥布霉素的混合抗生素佐剂的概念扩展到基于妥布霉素的嵌合体。嵌合体 （TOB-TOB-CIP）与环丙沙星、左氧氟沙星和莫西沙星对野生型和耐氟喹诺酮的 始终具有协同作用。此外，分别使用嵌合体 与头孢他啶/阿维巴坦、氨曲南/阿维巴坦和亚胺培南/雷利巴坦的三联组合，针对携带β-内酰胺酶的 ，达到了头孢他啶、氨曲南和亚胺培南的药敏折点。我们的研究结果表明，基于妥布霉素的嵌合体形成了一类新型的抗生素增效剂，能够恢复抗生素对 的活性。
