Definition of a Family of Nonmobile Colistin Resistance (NMCR-1) Determinants Suggests Aquatic Reservoirs for MCR-4.

Polymyxins, a family of cationic antimicrobial peptides, are recognized as a last-resort clinical option used in the treatment of lethal infections with carbapenem-resistant pathogens. A growing body of mobile colistin resistance (MCR) determinants renders colistin ineffective in the clinical and human sectors, posing a challenge to human health and food security. However, the origin and reservoir of the MCR family enzymes is poorly understood. Herein, a new family of nonmobile colistin resistance (from nmcr-1 to nmcr-1.8) from the aquatic bacterium Shewanella is reported. NMCR-1 (541aa) displays 62.78% identity to MCR-4. Genetic and structural analyses reveal that NMCR-1 shares a similar catalytic mechanism and functional motifs, both of which are required for MCR action and its resultant phenotypic resistance to polymyxin. Phylogeny and domain-swapping demonstrate that NMCR-1 is a progenitor of MCR-4 rather than MCR-1/2. Additionally, the experiment of bacterial growth and viability reveals that NMCR-1 promotes fitness cost as MCR-1/4 does in the recipient Escherichia coli. In summary, the finding suggests that the aquatic bacterium Shewanella (and even its associated aquaculture) is a reservoir for MCR-4 mobile colistin resistance.