Fitness costs of mobilised colistin resistance gene 3 (mcr-3): systematic review, epidemiological study, and functional analysis

作者：Lujie Liang, Yaxin Li, Lin Wang, Wenli Wang, Yihao Zhang, Hui Zhao, Yaxuan Wang, Lingxuan Lyu, Jiachen Li, Dianrong Zhou, Zhe Hu, Li-Zhen Luo, Guanxiu Wang, Jia Wan, Lin Xu, Meisong Li, Min Dai, Meiting Yang, Shun Xiong, Lan‐Lan Zhong, Fang Bai, Siyuan Feng, Guo‐Bao Tian · 发表于：EBioMedicine · 年份：2025 · DOI：10.1016/j.ebiom.2025.105923 · 被引用次数：3 · 研究领域：Antibiotic Resistance in Bacteria、Malaria Research and Control、Bacterial Genetics and Biotechnology

BACKGROUND: The rapid evolution and dissemination of mobilised colistin resistance gene (mcr) family has revealed as a severe threat to the global public health. Nevertheless, dramatic reduction in the prevalence of mcr-1, the major member of mcr family, was observed after the withdrawal of colistin in animal fodder in China since 2017, demonstrating that colistin acts as a selective stress to promote the dissemination of mcr-1. As the second largest lineage, mcr-3 was firstly discovered in 2017 and has been identified from numerous sources. However, whether the spreading of mcr-3 is driven by colistin remains unknown. METHODS: To this end, we investigated the global prevalence of mcr-3 from 2005 to 2022 by an up-to-date systematic review, along with a nation-wide epidemiological study to establish the change of mcr-3 prevalence in China before and after 2017. To investigate the fitness cost imposed by MCR-3 upon bacterial host, in vitro and in vivo competitive assays were employed, along with morphological study and fluorescent observation. Moreover, by replacing non-optimal codons with optimal codons, synonymous mutations were introduced into the 5'-coding regions of mcr-3 to study mechanisms accounting for the distinct fitness cost conferred by MCR-1 and MCR-3. Furthermore, by combining AlphaFold and molecular dynamics (MD) simulation, we provided a complete characterisation on the putative lipid A binding pocket localised at the linker domain of MCR-3. Crucially, inhibito...