Tracking Global Transmission Dynamics of the Plasmid-Mediated mcr Gene: A Genomic Epidemiological Analysis

The emergence and spread of mobile colistin resistance (<i>mcr</i>) genes pose a significant challenge in controlling multidrug-resistant Gram-negative pathogens. Understanding the epidemiology of <i>mcr</i>-carrying plasmids is essential for mitigating their dissemination across humans, animals, and the environment. To characterize their spatiotemporal dynamics on a global scale, we analyzed an extensive collection of 5,549 <i>mcr</i>-carrying plasmids spanning 1995 to the present. We found that cross-genera transmission patterns of <i>mcr</i>-carrying plasmids varied across four distinct periods. Initially, IncHI2/HI2A plasmids provided a survival advantage across genera and regions, followed by IncI2, and ultimately by IncX4. Moreover, the three plasmid lineages (i.e., IncX4, IncI2, and IncHI2/HI2A) have reached a stable distribution across diverse bacterial hosts and geographic regions through horizontal gene transfer and clonal expansion. By integrating sequence similarity clustering of plasmids and <i>mcr</i>-related genetic environments, we identified 79 cross-genus, 43 intra-<i>E. coli</i>, and 10 intra-<i>S. enterica</i> transmission units. Molecular dating analysis traced the origin of IncX4 plasmids to 1990 in animal hosts, with phylogenetic evidence indicating potential cross-host, -genus, and -region exchange. Notably, IncP1 plasmids emerged as important vectors of <i>mcr-1</i> and <i>mcr-3</i> spread, particularly in Southeast Asia, warranting enhanced surveillance. These findings provide critical insights into the global transmission networks of plasmid-mediated <i>mcr</i> genes and underscore the urgent need for coordinated interventions.