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Synergistic activity of rifampicin and polymyxin B against intracellular Gram-negative ESKAPE pathogens involves

Vallo Varik1,2, Gang Wang1, George Kritikos2

  • 1Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.

Antimicrobial Agents and Chemotherapy
|November 28, 2025
PubMed

Insights

The combination of polymyxin B and rifampicin shows synergy against difficult-to-treat Gram-negative bacteria, including intracellular pathogens. This antibiotic combination effectively targets resistant strains and offers a new strategy against persistent infections.

Area of Science:

  • Microbiology
  • Infectious Diseases
  • Pharmacology

Background:

  • Antibiotic-resistant bacteria, especially ESKAPE pathogens, are a significant global health concern.
  • Intracellular bacteria contribute to persistent infections and treatment challenges.
  • Combining rifampicin with polymyxins is a promising strategy against multidrug-resistant Gram-negative infections.

Purpose of the Study:

  • To evaluate the synergistic efficacy of polymyxin B and rifampicin against Gram-negative bacteria, including intracellular forms.
  • To investigate the mechanisms underlying the synergy and its effectiveness against resistant strains.
  • To explore the potential of this combination for treating intracellular bacterial infections.

Main Methods:

  • In vitro evaluation of polymyxin B and rifampicin combination against Gram-negative clinical isolates.
  • Testing in both extracellular and intracellular infection models.
  • Utilizing reverse genetics to identify bacterial mutants susceptible to the combination.

Main Results:

  • The combination demonstrated synergy against both extracellular and intracellular Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae.
  • Synergy was enhanced in acidic conditions mimicking the host vacuole.
  • The combination remained effective against strains resistant to rifampicin or polymyxin B.
  • Mutants susceptible to the combination exhibited altered membrane properties and increased oxidative damage.

Conclusions:

  • Polymyxin B and rifampicin combination is synergistic against key Gram-negative ESKAPE pathogens, including intracellular bacteria.
  • The combination offers a viable therapeutic option for hard-to-eradicate intracellular bacterial infections.
  • Understanding the molecular mechanisms provides insights into novel treatment strategies for resistant infections.
Keywords:
ESKAPE pathogensGram-negative bacteriadrug repurposingdrug-drug interactionintracellular infectionpolymyxin Brifampicin

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