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Published on: September 29, 2019
Polymyxin Stereochemistry and Its Role in Antibacterial Activity and Outer Membrane Disruption
Cornelis J Slingerland1, Ioli Kotsogianni1, Charlotte M J Wesseling1
1Biological Chemistry Group, Institute of Biology Leiden, Leiden University, Sylviusweg 72, 2333 BE Leiden, The Netherlands.
Abstract:
With increasing rates of resistance toward commonly used antibiotics, especially among Gram-negative bacteria, there is renewed interested in polymyxins. Polymyxins are lipopeptide antibiotics with potent anti-Gram-negative activity and are generally believed to target lipid A, the lipopolysaccharide (LPS) anchor found in the outer membrane of Gram-negative bacteria. To characterize the stereochemical aspects of their mechanism(s) of action, we synthesized the full enantiomers of polymyxin B and the polymyxin B nonapeptide (PMBN). Both compounds were compared with the natural compounds in biological and biophysical assays, revealing strongly reduced antibacterial activity for the enantiomeric species. The enantiomeric compounds also exhibit reduced LPS binding, lower outer membrane (OM) permeabilization, and loss of synergetic potential. These findings provide new insights into the stereochemical requirements underlying the mechanisms of action of polymyxin B and PMBN.
Insights
Researchers synthesized enantiomers of polymyxin B and PMBN to study their antibacterial mechanisms. The enantiomeric forms showed significantly reduced activity, highlighting the importance of stereochemistry in polymyxin action against Gram-negative bacteria.
Area of Science:
- Microbiology
- Medicinal Chemistry
- Biophysics
Background:
- Rising antibiotic resistance in Gram-negative bacteria necessitates novel therapeutic strategies.
- Polymyxins are crucial antibiotics targeting Gram-negative bacteria, primarily acting on lipopolysaccharide (LPS).
- Understanding the precise mechanism of polymyxin action is vital for developing new antimicrobial agents.
Purpose of the Study:
- To investigate the role of stereochemistry in the antibacterial mechanism of polymyxin B and polymyxin B nonapeptide (PMBN).
- To synthesize and characterize the full enantiomers of polymyxin B and PMBN.
- To compare the biological and biophysical properties of enantiomeric polymyxins with their natural counterparts.
Main Methods:
- Chemical synthesis of polymyxin B and PMBN enantiomers.
- Biological assays to assess antibacterial activity.
- Biophysical techniques to evaluate LPS binding, outer membrane permeabilization, and synergistic potential.
Main Results:
- Enantiomeric polymyxin B and PMBN exhibited significantly reduced antibacterial efficacy compared to natural forms.
- Reduced binding to LPS was observed for the enantiomeric compounds.
- Enantiomers showed diminished outer membrane permeabilization and loss of synergistic activity.
Conclusions:
- Stereochemistry is critical for the potent antibacterial activity of polymyxin B and PMBN.
- The specific spatial arrangement of polymyxins dictates their interaction with LPS and membrane disruption.
- These findings offer crucial insights for the rational design of novel polymyxin-based antibiotics.
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