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Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming

Antimicrobial resistance represents a significant world-wide health threat that is looming. To meet this challenge, new classes of antimicrobial agents and the redesign of existing ones will be required. This review summarizes some of the studies that have been carried out in my own laboratories inv...

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Detalles Bibliográficos
Autor principal: Regen, Steven L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828373/
https://www.ncbi.nlm.nih.gov/pubmed/33450850
http://dx.doi.org/10.3390/molecules26020374
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author Regen, Steven L.
author_facet Regen, Steven L.
author_sort Regen, Steven L.
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description Antimicrobial resistance represents a significant world-wide health threat that is looming. To meet this challenge, new classes of antimicrobial agents and the redesign of existing ones will be required. This review summarizes some of the studies that have been carried out in my own laboratories involving membrane-disrupting agents. A major discovery that we made, using a Triton X-100 as a prototypical membrane-disrupting molecule and cholesterol-rich liposomes as model systems, was that membrane disruption can occur by two distinct processes, depending on the state of aggregation of the attacking agent. Specifically, we found that monomers induced leakage, while attack by aggregates resulted in a catastrophic rupture of the membrane. This discovery led us to design of a series of derivatives of the clinically important antifungal agent, Amphotericin B, where we demonstrated the feasibility of separating antifungal from hemolytic activity by decreasing the molecule’s tendency to aggregate, i.e., by controlling its monomer concentration. Using an entirely different approach (i.e., a “taming” strategy), we found that by covalently attaching one or more facial amphiphiles (“floats”) to Amphotericin B, its aggregate forms were much less active in lysing red blood cells while maintaining high antifungal activity. The possibility of applying such “monomer control” and “taming” strategies to other membrane-disrupting antimicrobial agents is briefly discussed.
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spelling pubmed-78283732021-01-25 Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming Regen, Steven L. Molecules Review Antimicrobial resistance represents a significant world-wide health threat that is looming. To meet this challenge, new classes of antimicrobial agents and the redesign of existing ones will be required. This review summarizes some of the studies that have been carried out in my own laboratories involving membrane-disrupting agents. A major discovery that we made, using a Triton X-100 as a prototypical membrane-disrupting molecule and cholesterol-rich liposomes as model systems, was that membrane disruption can occur by two distinct processes, depending on the state of aggregation of the attacking agent. Specifically, we found that monomers induced leakage, while attack by aggregates resulted in a catastrophic rupture of the membrane. This discovery led us to design of a series of derivatives of the clinically important antifungal agent, Amphotericin B, where we demonstrated the feasibility of separating antifungal from hemolytic activity by decreasing the molecule’s tendency to aggregate, i.e., by controlling its monomer concentration. Using an entirely different approach (i.e., a “taming” strategy), we found that by covalently attaching one or more facial amphiphiles (“floats”) to Amphotericin B, its aggregate forms were much less active in lysing red blood cells while maintaining high antifungal activity. The possibility of applying such “monomer control” and “taming” strategies to other membrane-disrupting antimicrobial agents is briefly discussed. MDPI 2021-01-13 /pmc/articles/PMC7828373/ /pubmed/33450850 http://dx.doi.org/10.3390/molecules26020374 Text en © 2021 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Regen, Steven L.
Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming
title Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming
title_full Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming
title_fullStr Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming
title_full_unstemmed Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming
title_short Improving the Cellular Selectivity of a Membrane-Disrupting Antimicrobial Agent by Monomer Control and by Taming
title_sort improving the cellular selectivity of a membrane-disrupting antimicrobial agent by monomer control and by taming
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828373/
https://www.ncbi.nlm.nih.gov/pubmed/33450850
http://dx.doi.org/10.3390/molecules26020374
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