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Polymyxin Stereochemistry and Its Role in Antibacterial Activity and Outer Membrane Disruption

[Image: see text] 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...

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Autores principales: Slingerland, Cornelis J., Kotsogianni, Ioli, Wesseling, Charlotte M. J., Martin, Nathaniel I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9745799/
https://www.ncbi.nlm.nih.gov/pubmed/36342383
http://dx.doi.org/10.1021/acsinfecdis.2c00307
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author Slingerland, Cornelis J.
Kotsogianni, Ioli
Wesseling, Charlotte M. J.
Martin, Nathaniel I.
author_facet Slingerland, Cornelis J.
Kotsogianni, Ioli
Wesseling, Charlotte M. J.
Martin, Nathaniel I.
author_sort Slingerland, Cornelis J.
collection PubMed
description [Image: see text] 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.
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spelling pubmed-97457992022-12-14 Polymyxin Stereochemistry and Its Role in Antibacterial Activity and Outer Membrane Disruption Slingerland, Cornelis J. Kotsogianni, Ioli Wesseling, Charlotte M. J. Martin, Nathaniel I. ACS Infect Dis [Image: see text] 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. American Chemical Society 2022-11-07 2022-12-09 /pmc/articles/PMC9745799/ /pubmed/36342383 http://dx.doi.org/10.1021/acsinfecdis.2c00307 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Slingerland, Cornelis J.
Kotsogianni, Ioli
Wesseling, Charlotte M. J.
Martin, Nathaniel I.
Polymyxin Stereochemistry and Its Role in Antibacterial Activity and Outer Membrane Disruption
title Polymyxin Stereochemistry and Its Role in Antibacterial Activity and Outer Membrane Disruption
title_full Polymyxin Stereochemistry and Its Role in Antibacterial Activity and Outer Membrane Disruption
title_fullStr Polymyxin Stereochemistry and Its Role in Antibacterial Activity and Outer Membrane Disruption
title_full_unstemmed Polymyxin Stereochemistry and Its Role in Antibacterial Activity and Outer Membrane Disruption
title_short Polymyxin Stereochemistry and Its Role in Antibacterial Activity and Outer Membrane Disruption
title_sort polymyxin stereochemistry and its role in antibacterial activity and outer membrane disruption
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9745799/
https://www.ncbi.nlm.nih.gov/pubmed/36342383
http://dx.doi.org/10.1021/acsinfecdis.2c00307
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