Commercialized artemisinin derivatives combined with colistin protect against critical Gram-negative bacterial infection.
Commercialized artemisinin derivatives combined with colistin protect against critical Gram-negative bacterial infection.
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DOI：
10.1038/s42003-022-03898-5
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发表时间：
2022-09-08
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
--
作者：
mcr-1基因及其突变体的出现和传播极大地影响了粘菌素在临床环境中治疗耐药革兰氏阴性菌感染的有效使用。然而，目前没有临床上可用的协同粘菌素。在此，我们鉴定了青蒿素衍生物，如双氢青蒿素（DHA），其与粘菌素对大多数革兰氏阴性菌（FIC < 0.5）产生协同抗菌作用，而不会诱导耐药性，特别是那些携带mcr-1基因的革兰氏阴性菌。机理分析揭示DHA与MCR-1的活性中心直接结合而抑制MCR-1的活性。同时，转录组和电镜分析结果表明，DHA还可以同时影响鞭毛的组装和细菌的能量代谢。此外，在革兰氏阴性菌的小鼠感染模型中，联合治疗显示出显著的治疗益处，如通过改善的存活率、降低的发病率、减轻的病理损伤和降低的细菌负荷所示。由于人类专用疟疾药物给药的总体安全性，青蒿素衍生物是一类有前途的细菌耐药性和毒力的多靶点抑制剂，可用于延长粘菌素的使用寿命，并解决粘菌素严重细菌感染的不可避免性。抗疟疾药物青蒿素衍生物通过同时抑制MCR-1功能和阻碍鞭毛组装和能量代谢，与粘菌素对革兰氏阴性菌产生协同抗菌作用。
The emergence and spread of the mcr-1 gene and its mutants has immensely compromised the efficient usage of colistin for the treatment of drug-resistant Gram-negative bacterial infection in clinical settings. However, there are currently no clinically available colistin synergis. Here we identify artemisinin derivatives, such as dihydroartemisinin (DHA), that produces a synergistic antibacterial effect with colistin against the majority of Gram-negative bacteria (FIC < 0.5) without induced resistance, particularly those carrying the mcr-1 gene. Mechanism analysis reveals the direct engagement of DHA with the active center of MCR-1 to inhibit the activity of MCR-1. Meanwhile, the results from transcriptome and electron microscope analysis show that DHA could also simultaneously affect the flagellar assembly and the energy metabolism of bacteria. Moreover, in the mouse infection models of Gram-negative bacteria, combination therapy shows remarkable treatment benefits, as shown by an improved survival rate, reduced morbidity, alleviated pathological injury and decreased bacterial loading. Due to the generally safe profile of specialized malaria medication administration in humans, artemisinin derivatives are a promising class of multi-target inhibitors on bacterial resistance and virulence that can be used to extend the usage life of colistin and to tackle the inevitability of serious bacterial infection with colistin. The anti-malaria drugs artemisinin derivatives produce a synergistic antibacterial effect with colistin against Gram-negative bacteria by simultaneously inhibiting MCR-1 function and hindering flagella assembly and energy metabolism.
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影响因子：
5.9
作者：
Liu, Yuan;Jia, Yuqian;Wang, Zhiqiang
通讯作者：
Wang, Zhiqiang
DOI：
10.1111/1440-1681.13461
发表时间：
2021-01-19
影响因子：
2.9
作者：
Chen, Yan;Tao, Tingjun;Cha, Xushan
通讯作者：
Cha, Xushan
影响因子：
5.5
作者：
Salomon-Ferrer, Romelia;Goetz, Andreas W.;Walker, Ross C.
通讯作者：
Walker, Ross C.
影响因子：
3
作者：
Trott, Oleg;Olson, Arthur J.
通讯作者：
Olson, Arthur J.
影响因子：
3
作者：
Morris, Garrett M.;Huey, Ruth;Lindstrom, William;Sanner, Michel F.;Belew, Richard K.;Goodsell, David S.;Olson, Arthur J.
通讯作者：
Olson, Arthur J.