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Small molecule downregulation of PmrAB reverses lipid A modification and breaks colistin resistance

Tyler L Harris1, Roberta J Worthington, Lauren E Hittle

  • 1Department of Chemistry, North Carolina State University , Raleigh, North Carolina 27695, United States.

ACS Chemical Biology
|October 18, 2013
PubMed

Insights

This study introduces a novel adjuvant therapy that restores antibiotic effectiveness against multidrug-resistant bacteria. The compound targets colistin resistance in Gram-negative pathogens by modulating a key two-component system.

Area of Science:

  • Microbiology
  • Drug Discovery
  • Molecular Biology

Background:

  • Multi-drug resistant (MDR) bacterial infections, especially Gram-negative, pose a significant global health threat.
  • Existing antibiotics are losing efficacy, necessitating novel therapeutic strategies.
  • Adjuvant therapeutics offer a promising alternative by restoring the effectiveness of current antibiotics.

Purpose of the Study:

  • To identify and characterize a small molecule adjuvant that suppresses colistin resistance in MDR Gram-negative bacteria.
  • To elucidate the mechanism by which the adjuvant interferes with colistin resistance.
  • To evaluate the potential for resistance development to the combination therapy.

Main Methods:

  • Screening for small molecule adjuvants targeting colistin resistance.
  • Investigating the effect of the adjuvant on the expression of the pmrCAB operon.
  • Analyzing the modification of lipid A structure in response to the adjuvant.
  • Assessing the evolution of resistance in bacteria treated with colistin in combination with the adjuvant.

Main Results:

  • A novel small molecule adjuvant was identified that suppresses colistin resistance in MDR Acinetobacter baumannii and Klebsiella pneumoniae.
  • The compound was found to downregulate the pmrCAB operon, reversing phosphoethanolamine modification of lipid A.
  • No resistance evolved in either colistin-susceptible or colistin-resistant bacteria when treated with the combination therapy.

Conclusions:

  • This study presents the first definitive example of a compound that overcomes antibiotic resistance by directly modulating a two-component system.
  • The identified adjuvant restores colistin efficacy against MDR Gram-negative bacteria.
  • The lack of resistance evolution to the combination therapy suggests a durable therapeutic strategy.

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