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Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of Candida albicans Filamentation

Candida albicans remains the main etiologic agent of candidiasis, the most common fungal infection and now the third most frequent infection in U.S. hospitals. The scarcity of antifungal agents and their limited efficacy contribute to the unacceptably high morbidity and mortality rates associated wi...

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Autores principales: Romo, Jesus A., Pierce, Christopher G., Chaturvedi, Ashok K., Lazzell, Anna L., McHardy, Stanton F., Saville, Stephen P., Lopez-Ribot, Jose L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717394/
https://www.ncbi.nlm.nih.gov/pubmed/29208749
http://dx.doi.org/10.1128/mBio.01991-17
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author Romo, Jesus A.
Pierce, Christopher G.
Chaturvedi, Ashok K.
Lazzell, Anna L.
McHardy, Stanton F.
Saville, Stephen P.
Lopez-Ribot, Jose L.
author_facet Romo, Jesus A.
Pierce, Christopher G.
Chaturvedi, Ashok K.
Lazzell, Anna L.
McHardy, Stanton F.
Saville, Stephen P.
Lopez-Ribot, Jose L.
author_sort Romo, Jesus A.
collection PubMed
description Candida albicans remains the main etiologic agent of candidiasis, the most common fungal infection and now the third most frequent infection in U.S. hospitals. The scarcity of antifungal agents and their limited efficacy contribute to the unacceptably high morbidity and mortality rates associated with these infections. The yeast-to-hypha transition represents the main virulence factor associated with the pathogenesis of C. albicans infections. In addition, filamentation is pivotal for robust biofilm development, which represents another major virulence factor for candidiasis and further complicates treatment. Targeting pathogenic mechanisms rather than growth represents an attractive yet clinically unexploited approach in the development of novel antifungal agents. Here, we performed large-scale phenotypic screening assays with 30,000 drug-like small-molecule compounds within ChemBridge’s DIVERSet chemical library in order to identify small-molecule inhibitors of C. albicans filamentation, and our efforts led to the identification of a novel series of bioactive compounds with a common biaryl amide core structure. The leading compound of this series, N-[3-(allyloxy)-phenyl]-4-methoxybenzamide, was able to prevent filamentation under all liquid and solid medium conditions tested, suggesting that it impacts a common core component of the cellular machinery that mediates hypha formation under different environmental conditions. In addition to filamentation, this compound also inhibited C. albicans biofilm formation. This leading compound also demonstrated in vivo activity in clinically relevant murine models of invasive and oral candidiasis. Overall, our results indicate that compounds within this series represent promising candidates for the development of novel anti-virulence approaches to combat C. albicans infections.
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spelling pubmed-57173942017-12-14 Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of Candida albicans Filamentation Romo, Jesus A. Pierce, Christopher G. Chaturvedi, Ashok K. Lazzell, Anna L. McHardy, Stanton F. Saville, Stephen P. Lopez-Ribot, Jose L. mBio Research Article Candida albicans remains the main etiologic agent of candidiasis, the most common fungal infection and now the third most frequent infection in U.S. hospitals. The scarcity of antifungal agents and their limited efficacy contribute to the unacceptably high morbidity and mortality rates associated with these infections. The yeast-to-hypha transition represents the main virulence factor associated with the pathogenesis of C. albicans infections. In addition, filamentation is pivotal for robust biofilm development, which represents another major virulence factor for candidiasis and further complicates treatment. Targeting pathogenic mechanisms rather than growth represents an attractive yet clinically unexploited approach in the development of novel antifungal agents. Here, we performed large-scale phenotypic screening assays with 30,000 drug-like small-molecule compounds within ChemBridge’s DIVERSet chemical library in order to identify small-molecule inhibitors of C. albicans filamentation, and our efforts led to the identification of a novel series of bioactive compounds with a common biaryl amide core structure. The leading compound of this series, N-[3-(allyloxy)-phenyl]-4-methoxybenzamide, was able to prevent filamentation under all liquid and solid medium conditions tested, suggesting that it impacts a common core component of the cellular machinery that mediates hypha formation under different environmental conditions. In addition to filamentation, this compound also inhibited C. albicans biofilm formation. This leading compound also demonstrated in vivo activity in clinically relevant murine models of invasive and oral candidiasis. Overall, our results indicate that compounds within this series represent promising candidates for the development of novel anti-virulence approaches to combat C. albicans infections. American Society for Microbiology 2017-12-05 /pmc/articles/PMC5717394/ /pubmed/29208749 http://dx.doi.org/10.1128/mBio.01991-17 Text en Copyright © 2017 Romo et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Romo, Jesus A.
Pierce, Christopher G.
Chaturvedi, Ashok K.
Lazzell, Anna L.
McHardy, Stanton F.
Saville, Stephen P.
Lopez-Ribot, Jose L.
Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of Candida albicans Filamentation
title Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of Candida albicans Filamentation
title_full Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of Candida albicans Filamentation
title_fullStr Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of Candida albicans Filamentation
title_full_unstemmed Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of Candida albicans Filamentation
title_short Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of Candida albicans Filamentation
title_sort development of anti-virulence approaches for candidiasis via a novel series of small-molecule inhibitors of candida albicans filamentation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717394/
https://www.ncbi.nlm.nih.gov/pubmed/29208749
http://dx.doi.org/10.1128/mBio.01991-17
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