Different threats posed by two major mobilized colistin resistance genes — mcr-1.1 and mcr-3.1 — revealed through comparative genomic analysis

ABSTRACT: Objectives: Global spread of mobilized colistin resistance gene (mcr)-carrying Escherichia coli poses serious threats to public health. This study aimed to provide insights into different threats posed by two major mcr variants: mcr-1.1 and mcr-3.1. Methods: Genetic backgrounds and characteristics of mobile genetic elements carrying mcr-1.1 or mcr-3.1 in 74 (mcr)-carrying E. coli isolated from swine farms were analysed, and comparative genomic analysis was performed with the public sequence database. Results: The mcr-1.1 showed high horizontal transferability (6.30 logCFU/ml). Genetic background of mcr-1.1, including genetic cassette/plasmid, was transferred without insertion sequences (ISs) and/or multi-drug resistance (MDR) and highly shared across strains. The major mcr-1.1-cassette was “mcr-1.1-pap2”, mainly encoded in IncI2 and IncX4. Mcr-3.1 exhibited relatively lower conjugation frequency (0.97 logCFU/ml). The mcr-3.1-cassette was flanked by IS26 and was highly variable across strains because of the insertion, deletion, or truncation of IS6100, IS4321, or IS5075. Near the mcr-3.1 cassette, MDR regions consisting of antimicrobial/heavy metal resistance genes were identified, which varied across strains. From the MCR3-E13 strain, a mcr-3.1-carrying IncHI2-fragment was integrated into the bacterial chromosome via IS26-mediated co-integration. To our knowledge, this was the first study to describe that a mcr-3.1-carrying plasmid could be inserted into the bacterial chromosome. Conclusions: Based on high horizontal transferability, mcr-1.1 could play a major role on colistin resistance propagation. On the other hand, mcr-3.1 could be transmitted with MDR and have dual pathways mediated by plasmid transfer (horizontal transmission) and chromosomal insertion (vertical transmission), enabling it to proliferate stably despite its lower horizontal transferability