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Action and mechanism of the colistin resistance enzyme MCR-4.


ABSTRACT: 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 the action and mechanism of colistin resistance imparted by MCR-4, a recently-identified member from the broader MCR family. We found that MCR-4 originates from the silenced variant of Shewanella frigidimarina via progressive evolution and forms a phylogenetically-distinct group from the well-studied MCR-1/2 family. Domain-swapping experiments further confirmed that MCR-1 and MCR-4 transmembrane and catalytic domains are not functionally-interchangeable. However, structural and functional analyses demonstrated that MCR-4 possesses a similar PE lipid substrate-recognizable cavity and exploits an almost-identical ping-pong catalysis mechanism. MCR-4 also can alleviate colistin-triggered accumulation of reactive oxygen species (ROS). Taken together, this finding constitutes a functional proof that MCR-4 proceeds in a distinct evolutionary path to fulfill a consistent molecular mechanism, resulting in phenotypic colistin resistance.

SUBMITTER: Zhang H 

PROVIDER: S-EPMC6347640 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Action and mechanism of the colistin resistance enzyme MCR-4.

Zhang Huimin H   Hou Mengyun M   Xu Yongchang Y   Srinivas Swaminath S   Huang Man M   Liu Lizhang L   Feng Youjun Y  

Communications biology 20190125


Colistin is the last-resort antibiotic against lethal infections with multidrug-resistant bacterial pathogens. A rainbow coalition of mobile colistin resistance (<i>mcr</i>) genes raises global health concerns. Here, we describe the action and mechanism of colistin resistance imparted by MCR-4, a recently-identified member from the broader MCR family. We found that MCR-4 originates from the silenced variant of <i>Shewanella frigidimarina</i> via progressive evolution and forms a phylogenetically  ...[more]

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