Dataset Information

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

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.

SUBMITTER: Zhang H

PROVIDER: S-EPMC6548957 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Zhang Huimin H Wei Wenhui W Huang Man M Umar Zeeshan Z Feng Youjun Y

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20190403 11

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 resistan ...[more]

PMID: 31179218

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Project description:Antibiotic resistance is a prevalent problem in public health worldwide. In general, the carbapenem β-lactam antibiotics are considered a final resort against lethal infections by multidrug-resistant bacteria. Colistin is a cationic polypeptide antibiotic and acts as the last line of defense for treatment of carbapenem-resistant bacteria. Very recently, a new plasmid-borne colistin resistance gene, mcr-2, was revealed soon after the discovery of the paradigm gene mcr-1, which has disseminated globally. However, the molecular mechanisms for MCR-2 colistin resistance are poorly understood. Here we show a unique transposon unit that facilitates the acquisition and transfer of mcr-2 Evolutionary analyses suggested that both MCR-2 and MCR-1 might be traced to their cousin phosphoethanolamine (PEA) lipid A transferase from a known polymyxin producer, Paenibacillus Transcriptional analyses showed that the level of mcr-2 transcripts is relatively higher than that of mcr-1 Genetic deletions revealed that the transmembrane regions (TM1 and TM2) of both MCR-1 and MCR-2 are critical for their location and function in bacterial periplasm, and domain swapping indicated that the TM2 is more efficient than TM1. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) confirmed that all four MCR proteins (MCR-1, MCR-2, and two chimeric versions [TM1-MCR-2 and TM2-MCR-1]) can catalyze chemical modification of lipid A moiety anchored on lipopolysaccharide (LPS) with the addition of phosphoethanolamine to the phosphate group at the 4' position of the sugar. Structure-guided site-directed mutagenesis defined an essential 6-residue-requiring zinc-binding/catalytic motif for MCR-2 colistin resistance. The results further our mechanistic understanding of transferable colistin resistance, providing clues to improve clinical therapeutics targeting severe infections by MCR-2-containing pathogens.IMPORTANCE Carbapenem and colistin are the last line of refuge in fighting multidrug-resistant Gram-negative pathogens. MCR-2 is a newly emerging variant of the mobilized colistin resistance protein MCR-1, posing a potential challenge to public health. Here we report transfer of the mcr-2 gene by a unique transposal event and its possible origin. Distribution of MCR-2 in bacterial periplasm is proposed to be a prerequisite for its role in the context of biochemistry and the colistin resistance. We also define the genetic requirement of a zinc-binding/catalytic motif for MCR-2 colistin resistance. This represents a glimpse of transferable colistin resistance by MCR-2.

Dataset Information

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

Publications

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

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