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Novel polymyxin derivatives carrying only three positive charges are effective antibacterial agents

Martti Vaara1, John Fox, Günther Loidl

  • 1Northern Antibiotics Ltd, Helsinki, Finland. martti.vaara@northernantibiotics.com

Antimicrobial Agents and Chemotherapy
|July 2, 2008
PubMed

Insights

Novel polymyxin derivatives with fewer positive charges show potent antibacterial activity against multidrug-resistant gram-negative bacteria. These compounds exhibit reduced nephrotoxicity, offering a promising alternative to existing last-resort antibiotics.

Area of Science:

  • Microbiology
  • Pharmacology
  • Medicinal Chemistry

Background:

  • Polymyxins are last-resort antibiotics for multidrug-resistant gram-negative infections.
  • Polymyxin nephrotoxicity limits clinical use.
  • Nephrotoxicity may stem from the highly cationic nature of polymyxins.

Purpose of the Study:

  • To develop novel polymyxin derivatives with reduced positive charges.
  • To evaluate the antibacterial efficacy and nephrotoxicity of these derivatives.

Main Methods:

  • Synthesized polymyxin derivatives with three positive charges (e.g., NAB739).
  • Assessed antibacterial activity (MICs) against Gram-negative bacteria, including Escherichia coli, Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa.
  • Investigated synergistic effects with other antibiotics.
  • Measured binding affinity to rat kidney brush border membrane.

Main Results:

  • Novel derivatives (e.g., NAB739) exhibited potent activity against polymyxin-susceptible strains, comparable to polymyxin B.
  • NAB739 sensitized Acinetobacter baumannii to various antibiotics at subinhibitory concentrations.
  • NAB740 showed high activity against Pseudomonas aeruginosa.
  • Derivatives demonstrated significantly lower affinities for kidney membranes compared to polymyxin B, suggesting reduced nephrotoxicity.

Conclusions:

  • Reduced positive charge in polymyxin derivatives maintains antibacterial efficacy while potentially decreasing nephrotoxicity.
  • These novel compounds represent promising candidates for treating challenging multidrug-resistant Gram-negative infections.

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