Novel des-fatty acyl-polymyxin B derivatives with Pseudomonas aeruginosa-specific antimicrobial activity

Area of Science:

• Medicinal Chemistry
• Microbiology
• Pharmacology

Background:

• Polymyxin B (PMB) is a critical cationic cyclic decapeptide antibiotic.
• PMB features a fatty acyl (FA) modification at the α-amino group of Dab¹.
• Structure-activity relationship studies are vital for developing novel peptide antibiotics.

Purpose of the Study:

• To synthesize and evaluate des-fatty acyl Polymyxin B derivatives.
• To investigate the impact of N-terminal modifications on antimicrobial and lipopolysaccharide (LPS) binding activities.
• To assess the in vivo acute toxicity of novel PMB analogs.

Main Methods:

• Synthesis of ten des-FA PMB derivatives with varied N-terminal moieties.
• Antimicrobial activity testing against Pseudomonas aeruginosa.
• Lipopolysaccharide (LPS) binding assays using Escherichia coli and P. aeruginosa.
• Acute toxicity evaluation in mice via intravenous administration.

Main Results:

• Several analogs exhibited potent antimicrobial activity against P. aeruginosa, some equivalent to PMB.
• LPS binding activity correlated with the number of positive charges available for binding.
• Peptides with basic side chains showed comparable LPS binding to PMB.
• Specific derivatives like [Ser²-Dap³]-PMB(2-10) demonstrated significantly lower acute toxicity than PMB.

Conclusions:

• N-terminal modification of PMB can yield analogs with improved antimicrobial efficacy and reduced toxicity.
• Charge and basic side chains are crucial for LPS binding and antimicrobial activity.
• These findings contribute to the development of safer and more effective Polymyxin B-based antibiotics.