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Synergetic Antimicrobial Activity and Mechanism of Clotrimazole-Linked CO-Releasing Molecules
[Image: see text] Several metal-based carbon monoxide-releasing molecules (CORMs) are active CO donors with established antibacterial activity. Among them, CORM conjugates with azole antibiotics of type [Mn(CO)(3)(2,2′-bipyridyl)(azole)](+) display important synergies against several microbes. We ca...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9389576/ https://www.ncbi.nlm.nih.gov/pubmed/35996473 http://dx.doi.org/10.1021/acsbiomedchemau.2c00007 |
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author | Mendes, Sofia S. Marques, Joana Mesterházy, Edit Straetener, Jan Arts, Melina Pissarro, Teresa Reginold, Jorgina Berscheid, Anne Bornikoel, Jan Kluj, Robert M. Mayer, Christoph Oesterhelt, Filipp Friães, Sofia Royo, Beatriz Schneider, Tanja Brötz-Oesterhelt, Heike Romão, Carlos C. Saraiva, Lígia M. |
author_facet | Mendes, Sofia S. Marques, Joana Mesterházy, Edit Straetener, Jan Arts, Melina Pissarro, Teresa Reginold, Jorgina Berscheid, Anne Bornikoel, Jan Kluj, Robert M. Mayer, Christoph Oesterhelt, Filipp Friães, Sofia Royo, Beatriz Schneider, Tanja Brötz-Oesterhelt, Heike Romão, Carlos C. Saraiva, Lígia M. |
author_sort | Mendes, Sofia S. |
collection | PubMed |
description | [Image: see text] Several metal-based carbon monoxide-releasing molecules (CORMs) are active CO donors with established antibacterial activity. Among them, CORM conjugates with azole antibiotics of type [Mn(CO)(3)(2,2′-bipyridyl)(azole)](+) display important synergies against several microbes. We carried out a structure–activity relationship study based upon the lead structure of [Mn(CO)(3)(Bpy)(Ctz)](+) by producing clotrimazole (Ctz) conjugates with varying metal and ligands. We concluded that the nature of the bidentate ligand strongly influences the bactericidal activity, with the substitution of bipyridyl by small bicyclic ligands leading to highly active clotrimazole conjugates. On the contrary, the metal did not influence the activity. We found that conjugate [Re(CO)(3)(Bpy)(Ctz)](+) is more than the sum of its parts: while precursor [Re(CO)(3)(Bpy)Br] has no antibacterial activity and clotrimazole shows only moderate minimal inhibitory concentrations, the potency of [Re(CO)(3)(Bpy)(Ctz)](+) is one order of magnitude higher than that of clotrimazole, and the spectrum of bacterial target species includes Gram-positive and Gram-negative bacteria. The addition of [Re(CO)(3)(Bpy)(Ctz)](+) to Staphylococcus aureus causes a general impact on the membrane topology, has inhibitory effects on peptidoglycan biosynthesis, and affects energy functions. The mechanism of action of this kind of CORM conjugates involves a sequence of events initiated by membrane insertion, followed by membrane disorganization, inhibition of peptidoglycan synthesis, CO release, and break down of the membrane potential. These results suggest that conjugation of CORMs to known antibiotics may produce useful structures with synergistic effects that increase the conjugate’s activity relative to that of the antibiotic alone. |
format | Online Article Text |
id | pubmed-9389576 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-93895762022-08-20 Synergetic Antimicrobial Activity and Mechanism of Clotrimazole-Linked CO-Releasing Molecules Mendes, Sofia S. Marques, Joana Mesterházy, Edit Straetener, Jan Arts, Melina Pissarro, Teresa Reginold, Jorgina Berscheid, Anne Bornikoel, Jan Kluj, Robert M. Mayer, Christoph Oesterhelt, Filipp Friães, Sofia Royo, Beatriz Schneider, Tanja Brötz-Oesterhelt, Heike Romão, Carlos C. Saraiva, Lígia M. ACS Bio Med Chem Au [Image: see text] Several metal-based carbon monoxide-releasing molecules (CORMs) are active CO donors with established antibacterial activity. Among them, CORM conjugates with azole antibiotics of type [Mn(CO)(3)(2,2′-bipyridyl)(azole)](+) display important synergies against several microbes. We carried out a structure–activity relationship study based upon the lead structure of [Mn(CO)(3)(Bpy)(Ctz)](+) by producing clotrimazole (Ctz) conjugates with varying metal and ligands. We concluded that the nature of the bidentate ligand strongly influences the bactericidal activity, with the substitution of bipyridyl by small bicyclic ligands leading to highly active clotrimazole conjugates. On the contrary, the metal did not influence the activity. We found that conjugate [Re(CO)(3)(Bpy)(Ctz)](+) is more than the sum of its parts: while precursor [Re(CO)(3)(Bpy)Br] has no antibacterial activity and clotrimazole shows only moderate minimal inhibitory concentrations, the potency of [Re(CO)(3)(Bpy)(Ctz)](+) is one order of magnitude higher than that of clotrimazole, and the spectrum of bacterial target species includes Gram-positive and Gram-negative bacteria. The addition of [Re(CO)(3)(Bpy)(Ctz)](+) to Staphylococcus aureus causes a general impact on the membrane topology, has inhibitory effects on peptidoglycan biosynthesis, and affects energy functions. The mechanism of action of this kind of CORM conjugates involves a sequence of events initiated by membrane insertion, followed by membrane disorganization, inhibition of peptidoglycan synthesis, CO release, and break down of the membrane potential. These results suggest that conjugation of CORMs to known antibiotics may produce useful structures with synergistic effects that increase the conjugate’s activity relative to that of the antibiotic alone. American Chemical Society 2022-04-08 /pmc/articles/PMC9389576/ /pubmed/35996473 http://dx.doi.org/10.1021/acsbiomedchemau.2c00007 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Mendes, Sofia S. Marques, Joana Mesterházy, Edit Straetener, Jan Arts, Melina Pissarro, Teresa Reginold, Jorgina Berscheid, Anne Bornikoel, Jan Kluj, Robert M. Mayer, Christoph Oesterhelt, Filipp Friães, Sofia Royo, Beatriz Schneider, Tanja Brötz-Oesterhelt, Heike Romão, Carlos C. Saraiva, Lígia M. Synergetic Antimicrobial Activity and Mechanism of Clotrimazole-Linked CO-Releasing Molecules |
title | Synergetic Antimicrobial Activity and Mechanism of
Clotrimazole-Linked CO-Releasing Molecules |
title_full | Synergetic Antimicrobial Activity and Mechanism of
Clotrimazole-Linked CO-Releasing Molecules |
title_fullStr | Synergetic Antimicrobial Activity and Mechanism of
Clotrimazole-Linked CO-Releasing Molecules |
title_full_unstemmed | Synergetic Antimicrobial Activity and Mechanism of
Clotrimazole-Linked CO-Releasing Molecules |
title_short | Synergetic Antimicrobial Activity and Mechanism of
Clotrimazole-Linked CO-Releasing Molecules |
title_sort | synergetic antimicrobial activity and mechanism of
clotrimazole-linked co-releasing molecules |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9389576/ https://www.ncbi.nlm.nih.gov/pubmed/35996473 http://dx.doi.org/10.1021/acsbiomedchemau.2c00007 |
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