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N-terminal modifications of Polymyxin B nonapeptide and their effect on antibacterial activity
1Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.
Abstract:
Polymyxin B (PMB) is a potent antibacterial lipopeptide composed of a positively charged cyclic peptide ring and a fatty acid containing tail. Polymyxin B nonapeptide (PMBN), the deacylated amino derivative of polymyxin B, is much less bactericidal but able to permeabilize the outer membrane of Gram-negative bacteria and to neutralize the toxic effects of lipopolysaccharide (LPS). In this study, we synthesized and evaluated the antibacterial and LPS neutralizing activities of four PMBN analogs modified at their N-terminal. Our results suggest that oligoalanyl substitutions of PMBN do not effect most of PMBN activities. However, a hydrophobic aromatic substitution generated a PMB-like molecule with high antibacterial activity and significant reduced toxicity.
Insights
Polymyxin B nonapeptide (PMBN) analogs were synthesized to enhance antibacterial activity. A specific hydrophobic substitution yielded a molecule with potent antibacterial effects and reduced toxicity, similar to Polymyxin B (PMB).
Area of Science:
- Medicinal Chemistry
- Microbiology
- Drug Discovery
Background:
- Polymyxin B (PMB) is a lipopeptide antibiotic effective against Gram-negative bacteria.
- Polymyxin B nonapeptide (PMBN), a derivative of PMB, retains outer membrane permeabilization and lipopolysaccharide (LPS) neutralization but has reduced bactericidal activity.
- Modifications to PMBN are explored to improve its therapeutic potential.
Purpose of the Study:
- To synthesize and evaluate N-terminally modified Polymyxin B nonapeptide (PMBN) analogs.
- To assess the antibacterial activity and lipopolysaccharide (LPS) neutralizing capacity of these novel PMBN analogs.
- To identify modifications that enhance antibacterial potency while mitigating toxicity.
Main Methods:
- Synthesis of four N-terminally modified PMBN analogs.
- Evaluation of antibacterial activity against Gram-negative bacteria.
- Assessment of lipopolysaccharide (LPS) neutralization capabilities.
- Toxicity evaluation of the synthesized analogs.
Main Results:
- Oligoalanyl substitutions on PMBN showed minimal impact on its activity.
- A PMBN analog with a hydrophobic aromatic substitution exhibited potent antibacterial activity.
- This hydrophobic analog demonstrated significantly reduced toxicity compared to native PMBN.
- The modified PMBN analog mimicked the activity profile of Polymyxin B (PMB).
Conclusions:
- N-terminal modification of PMBN can yield analogs with enhanced properties.
- Hydrophobic aromatic substitutions represent a promising strategy for developing potent and less toxic Polymyxin B (PMB)-like antibacterial agents.
- Further research into these modified PMBN analogs could lead to new therapeutic options for Gram-negative infections.