Department of Respiratory Medicine, Center for Pathogen Biology and Infectious Diseases, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, 130021, Jilin, China.
State Key Laboratory for Zoonotic Diseases, College of Veterinary Medicine, Jilin University, Changchun, 130062, Jilin, China.
Commun Biol. 2022 Sep 8;5(1):931. doi: 10.1038/s42003-022-03898-5.
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.
mcr-1 基因及其突变体的出现和传播极大地影响了黏菌素在临床治疗耐药革兰氏阴性菌感染中的有效应用。然而，目前尚无临床可用的黏菌素协同剂。在这里，我们发现青蒿素衍生物，如双氢青蒿素（DHA），与黏菌素联合使用对大多数革兰氏阴性菌（FIC<0.5）具有协同抗菌作用，而不会产生诱导耐药性，特别是那些携带 mcr-1 基因的细菌。机制分析表明 DHA 直接与 MCR-1 的活性中心结合，从而抑制 MCR-1 的活性。同时，转录组和电子显微镜分析的结果表明，DHA 还可以同时影响细菌的鞭毛组装和能量代谢。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，表现为提高了生存率、降低了发病率、减轻了病理损伤和减少了细菌负荷。由于青蒿素类药物在人类中的使用具有普遍的安全性，青蒿素衍生物是一类有前途的多靶点抑制剂，可以用于延长黏菌素的使用寿命，并解决严重的革兰氏阴性菌感染问题。
