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Polymyxin B adjuvants against polymyxin B- and carbapenem-resistant Gram-negative bacteria

João Paulo Salvaterra Pasquini1, Paula Assis Queiroz1, Pedro Henrique Rodrigues do Amaral2

  • 1Postgraduate Program in Bioscience & Physiopathology, State University of Maringa, Maringa, Parana, Brazil.

Future Microbiology
|September 11, 2024
PubMed

Insights

New dinitrobenzoic acid derivatives (DNH) show promise as adjuvants to restore Polymyxin B (PMB) efficacy against carbapenem-resistant Gram-negative bacteria (CR-GNB). These compounds significantly enhance PMB activity, offering a potential strategy against difficult-to-treat infections.

Area of Science:

  • Microbiology
  • Pharmacology
  • Infectious Diseases

Background:

  • Polymyxin B (PMB) is a critical antibiotic for carbapenem-resistant Gram-negative bacteria (CR-GNB) infections.
  • Emerging resistance to PMB necessitates novel therapeutic strategies, including antibiotic adjuvants.

Purpose of the Study:

  • To evaluate 3,5-dinitrobenzoic acid derivatives (DNH) and isoniazid-N-acylhydrazones (INZ) as adjuvants to enhance PMB efficacy against CR-GNB.
  • To investigate the mechanisms by which DNH derivatives restore PMB activity.

Main Methods:

  • Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) assays.
  • Drug combination assays using clinical isolates of Enterobacterales and Acinetobacter baumannii.
  • Flow cytometry and scanning electron microscopy (SEM) to assess cellular effects.

Main Results:

  • DNH01, DNH11, and DNH20 restored PMB activity in 80% of tested CR-GNB isolates (MIC ≤ 2 μg/ml).
  • DNH derivatives enabled PMB to be effective at 256-fold lower concentrations.
  • Flow cytometry and SEM confirmed enhanced PMB activity with DNH derivatives.

Conclusions:

  • DNH derivatives are promising adjuvants for enhancing PMB efficacy against PMB-resistant CR-GNB.
  • These compounds offer a potential therapeutic avenue to combat challenging Gram-negative bacterial infections.
Keywords:
3,5-dinitrobenzoylhydrazonic derivativesbacterial resistanceenterobacteralesisoniazid-acylhydrazones derivativespolymyxin

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