Action and mechanism of the colistin resistance enzyme MCR-4

摘要: Colistin is the last-resort antibiotic against lethal infections with multidrug-resistant bacterial pathogens. A rainbow coalition of mobile colistin resistance (mcr) genes raises global health concerns. Here, we describe action and mechanism imparted by MCR-4, a recently-identified member from broader MCR family. We found that MCR-4 originates silenced variant Shewanella frigidimarina via progressive evolution forms phylogenetically-distinct group well-studied MCR-1/2 Domain-swapping experiments further confirmed MCR-1 transmembrane catalytic domains are not functionally-interchangeable. However, structural functional analyses demonstrated possesses similar PE lipid substrate-recognizable cavity exploits an almost-identical ping-pong catalysis mechanism. also can alleviate colistin-triggered accumulation reactive oxygen species (ROS). Taken together, this finding constitutes proof proceeds in distinct evolutionary path to fulfill consistent molecular mechanism, resulting phenotypic resistance.