The wide dissemination of multidrug-resistant (MDR) Gram-negative bacteria poses a significant global health and security concern. As developing new antibiotics is generally costly, fastidious, and time-consuming, there is an urgent need for alternative therapeutic strategies to address the gap in antibiotic discovery void. This study aimed to investigate the activity of colistin (CS) in combination with a natural product, rutin (RT), to combat against Salmonella Typhimurium (S. Tm) in vitro and in vivo. The results showed that a combination with RT enabled the potentiation of CS efficacy. Further mechanistic analysis indicated that RT disrupted iron homeostasis to inactivate the PmrA/PmrB system, thereafter reducing the bacterial membrane modifications for enhancing CS binding. Besides enhancing bactericidal activity of CS, RT was also observed to mitigate the CS-induced nephrotoxicity, by which the dosing limitation of CS was overcome for better pathogen clearance. The animal trial eventually confirmed the in vivo synergistic interaction of RT with CS to treat the bacterial infection. To sum up, the present study uncovered the potential of RT as a viable adjuvant of CS to eradicate the infection and protect the hosts, which might serve as a promising alternative to combat infections caused by MDR Gram-negative bacteria.

中文翻译：

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芦丁与粘菌素协同作用，通过增强疗效和降低毒性来根除小鼠沙门氏菌病


多重耐药 （MDR） 革兰氏阴性菌的广泛传播构成了严重的全球健康和安全问题。由于开发新抗生素通常成本高昂、要求苛刻且耗时，因此迫切需要替代治疗策略来填补抗生素发现空白的空白。本研究旨在研究粘菌素 （CS） 与天然产物芦丁 （RT） 联合使用在体外和体内对抗鼠伤寒沙门氏菌 （S. Tm） 的活性。结果表明，与 RT 联合使用可以增强 CS 疗效。进一步的机制分析表明，RT 破坏铁稳态以灭活 PmrA/PmrB 系统，从而减少细菌膜修饰以增强 CS 结合。除了增强 CS 的杀菌活性外，还观察到 RT 可以减轻 CS 诱导的肾毒性，从而克服 CS 的剂量限制以更好地清除病原体。动物试验最终证实了 RT 与 CS 在体内协同作用治疗细菌感染。综上所述，本研究揭示了 RT 作为 CS 的可行佐剂根除感染和保护宿主的潜力，这可能作为对抗 MDR 革兰氏阴性菌引起的感染的有前途的替代方案。