Abstract
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.
Highlights
Polymyxins, a family of cationic antimicrobial peptides, are recognized as a an ability of binding to its initial target, the negatively charged lipid A moiety of last-resort clinical option used in the treatment of lethal infections with carlipopolysaccharides (LPS-lipid A) anchored bapenem-resistant pathogens
As suggested by the nomenclature committee in National Center for Biotechnology Information (NCBI), we thereafter renamed the lptA of S. algae MARS14 into nmcr-1, an abbreviation for nonmobile colistin resistance determinant
Polymerase chain reaction (PCR) detection with a pair of specific nmcr-1 primers (Table S1, Supporting Information) demonstrated that nmcr-1 is present in S. algae, but not S. oneidensis (Figure 2A)
Summary
Though comparative genomics recently proposed that the locus SO_2048 (541aa) of S. algae encodes a putative PEA-lipid A transferase (LptA, called EptA),[54,56] a complete set of genetic and biochemical evidence is lacking. We notice that Shewanella oneidensis (S. oneidensis) MR-1 retains a lptA locus [SO_2048, 541aa] neighboring with SO_2047 (S9 protein of prolyl oligo-peptidase family) at the 5′-end, and SO_2049 (diguanylate cyclase) at the 3′-end Despite that it is annotated as a sulfatase with the domain of unknown function (DUF1705), belonging to the pfam08019 family, the S. oneidensis LptA has only 66.5% identity to the counterpart in S. algae MARS14. Using the nmcr-1 sequence (nucleic acids and amino acids) as a probe, we searched the sequence database of all the known genomes (and/or contigs) within the genus Shewanella As a result, it returned significant hits of over 94% identity in seven additional species/strains (such as Shewanella upenei (S. upenei) andShewanella indica (S. indica) of Shewanellaceae; Figures S1 and S2, Supporting Information). It constitutes a functional proof that NMCR-1 is a representative for a newly identified nonmobile colistin resistance exclusively restricted to certain species of Shewanella
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