Commercialized artemisinin derivatives combined with colistin protect against critical Gram-negative bacterial infection

作者：Yonglin Zhou, Baichen Liu, Xiuling Chu, Jianqing Su, Lei Xu, Li Li, Xuming Deng, Dan Li, Qianghua Lv, Jianfeng Wang · 发表于：Communications Biology · 年份：2022 · DOI：10.1038/s42003-022-03898-5 · 被引用次数：33 · 研究领域：Malaria Research and Control、Antibiotic Resistance in Bacteria、Computational Drug Discovery Methods

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.