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Development of des-fatty acyl-polymyxin B decapeptide analogs with Pseudomonas aeruginosa-specific antimicrobial

Naoko Katsuma1, Yuki Sato, Kazuhiro Ohki

  • 1Faculty of Pharmaceutical Sciences, Hokuriku University, Kunazawa, Japan.

Chemical & Pharmaceutical Bulletin
|April 2, 2009
PubMed

Insights

New polymyxin B analogs show potent activity against Pseudomonas aeruginosa. These Des-FA-PMB compounds exhibit reduced toxicity and specific antimicrobial effects, offering potential for novel antibacterial therapies.

Area of Science:

  • Medicinal Chemistry
  • Microbiology
  • Pharmacology

Background:

  • Polymyxin B (PMB) is a crucial antibiotic for treating infections caused by Gram-negative bacteria.
  • Development of novel PMB analogs is essential to combat rising antibiotic resistance and reduce toxicity.
  • Des-fatty acyl-polymyxin B (Des-FA-PMB) analogs offer a platform for structural modification to enhance antimicrobial properties.

Purpose of the Study:

  • To synthesize and evaluate N-terminal analogs of des-fatty acyl-polymyxin B (Des-FA-[X(1)]-PMB).
  • To assess the antimicrobial activity of these analogs against Escherichia coli, Salmonella Typhimurium, and Pseudomonas aeruginosa.
  • To investigate the lipopolysaccharide (LPS)-binding activity and acute toxicity of promising Des-FA-PMB analogs.

Main Methods:

  • Synthesis of twelve N-terminal analogs of Des-FA-PMB, varying the amino acid or peptide at position 1.
  • Determination of minimum inhibitory concentrations (MICs) against E. coli, S. Typhimurium, and P. aeruginosa.
  • Evaluation of LPS-binding activity and acute toxicity using mouse tail intravenous administration tests (LD50 determination).

Main Results:

  • Des-FA-[Dap(1)]-, Des-FA-[Ser(1)]-, Des-FA-[Dab-Dab-Dab(1)]-, and Des-FA-[Arg-Arg-Arg(1)]-PMB demonstrated potent activity (MICs 0.5-1 nmol/ml) exclusively against P. aeruginosa.
  • Analogs with Lys, Arg, Leu, or Ala at position 1 showed no improved activity compared to lead compounds or PMB.
  • Des-FA-[Dap(1)]-PMB and Des-FA-[Trp(1)]-PMB exhibited significantly reduced acute toxicity (LD50 23.5 and 19.0 µmol/kg) compared to PMB (LD50 4.8 µmol/kg).

Conclusions:

  • Compact hydrophilic amino acids or basic tripeptides at the N-terminus confer specific bactericidal activity against P. aeruginosa.
  • Certain Des-FA-PMB analogs display potent antimicrobial activity and reduced toxicity, suggesting their potential as therapeutic agents.
  • These findings highlight the importance of N-terminal modifications in developing safer and more effective polymyxin-based antibiotics.

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