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Overcoming mcr-1 mediated colistin resistance with colistin in combination with other antibiotics

Craig R MacNair1, Jonathan M Stokes1, Lindsey A Carfrae1

  • 1Michael G. DeGroote Institute for Infectious Disease Research, Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8N 3ZS, Canada.

Nature Communications
|February 2, 2018
PubMed

Insights

The mcr-1 gene confers colistin resistance but potentiates other antibiotics against Gram-negative bacteria. Combination therapy with colistin shows promise for treating highly drug-resistant infections.

Area of Science:

  • Microbiology
  • Infectious Diseases
  • Pharmacology

Background:

  • Plasmid-mediated colistin resistance (mcr-1) is a growing threat, potentially driving the spread of pan-resistant Gram-negative bacteria.
  • Colistin is a last-resort antibiotic, and resistance limits treatment options for severe Gram-negative infections.

Purpose of the Study:

  • To investigate the impact of mcr-1 mediated colistin resistance on bacterial susceptibility to colistin and other antibiotics.
  • To evaluate the therapeutic potential of combination therapies involving colistin against mcr-1 positive Gram-negative bacteria.

Main Methods:

  • Assessing colistin's effect on mcr-1 expressing Enterobacteriaceae outer membrane integrity and cell death.
  • Testing the synergistic effects of colistin combined with various antibiotics against Gram-negative bacteria.
  • Evaluating the efficacy of colistin-clarithromycin combination therapy in murine infection models (thigh and bacteremia).

Main Results:

  • mcr-1 confers resistance to colistin-induced cell death but minimally impacts outer membrane disruption.
  • Colistin potentiates antibiotics not typically active against Gram-negative bacteria, enabling growth inhibition below clinical breakpoints.
  • Combination therapy of colistin and clarithromycin demonstrated efficacy against mcr-1 positive Klebsiella pneumoniae in vivo.

Conclusions:

  • Colistin combination therapy with antibiotics usually targeting Gram-positive bacteria offers a viable strategy against highly drug-resistant Gram-negative pathogens.
  • This approach could provide new therapeutic avenues for infections caused by mcr-1 expressing bacteria.

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