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Molecular Insights into Functional Differences between mcr-3- and mcr-1-Mediated Colistin Resistance

Hui Li1,2, Lu Yang1, Zhihai Liu1

  • 1Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China.

Antimicrobial Agents and Chemotherapy
|July 11, 2018
PubMed

Insights

The study reveals functional differences between colistin resistance genes mcr-3 and mcr-1. MCR-3 shows greater thermostability and a distinct catalytic mechanism, offering insights into combating multidrug-resistant bacteria.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Biochemistry

Background:

  • Plasmid-mediated colistin resistance genes, mcr-1 and mcr-3, pose a significant threat to treating multidrug-resistant Gram-negative bacterial infections.
  • Understanding the functional distinctions between MCR-1 and MCR-3 is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To elucidate the molecular and functional differences between MCR-3 and MCR-1 in mediating colistin resistance.
  • To investigate the catalytic mechanism and substrate recognition of the MCR-3 enzyme.

Main Methods:

  • Comparative protein sequence alignment using Clustal Omega.
  • Homology modeling and molecular docking to study MCR-3-lipid A interactions.
  • Site-directed mutagenesis to identify key catalytic residues.
  • Electrospray ionization-time of flight mass spectrometry to confirm lipid A modification.
  • Far-UV circular dichroism spectroscopy to assess enzyme thermostability.

Main Results:

  • Identified sequence divergence between MCR-1 and MCR-3.
  • Validated Thr277 in MCR-3 as a key nucleophilic residue in catalysis.
  • Confirmed lipid A modification by both MCR-3 and MCR-1 enzymes.
  • Demonstrated that MCR-3 exhibits higher thermostability (Tm = 66.19°C) than MCR-1 (Tm = 61.14°C).

Conclusions:

  • MCR-3 and MCR-1 possess distinct functional properties contributing to colistin resistance.
  • The findings provide a molecular basis for the differences in colistin resistance conferred by mcr-3 and mcr-1.
  • Enhanced understanding of MCR-3 function and stability may inform future drug development against resistant pathogens.
Keywords:
colistin resistancehomology modelingmcr-1mcr-3phosphatidylethanolamine

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