Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of <italic toggle="yes">Candida albicans</italic> Filamentation

ABSTRACT 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 asso...

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Autores principales:	Jesus A. Romo, Christopher G. Pierce, Ashok K. Chaturvedi, Anna L. Lazzell, Stanton F. McHardy, Stephen P. Saville, Jose L. Lopez-Ribot
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Candida albicans anti-virulence factor antifungal drugs filamentation large-scale phenotypic screening Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/69248be2b72a44429a21da8645afd8de
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spelling	oai:doaj.org-article:69248be2b72a44429a21da8645afd8de2021-11-15T15:51:55ZDevelopment of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of <italic toggle="yes">Candida albicans</italic> Filamentation10.1128/mBio.01991-172150-7511https://doaj.org/article/69248be2b72a44429a21da8645afd8de2017-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01991-17https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE Since fungi are eukaryotes, there is a limited number of fungus-specific targets and, as a result, the antifungal arsenal is exceedingly small. Furthermore, the efficacy of antifungal treatment is compromised by toxicity and development of resistance. As a consequence, fungal infections carry high morbidity and mortality rates, and there is an urgent but unmet need for novel antifungal agents. One appealing strategy for antifungal drug development is to target pathogenetic mechanisms associated with infection. In Candida albicans, one of the most common pathogenic fungi, morphogenetic transitions between yeast cells and filamentous hyphae represent a key virulence factor associated with the ability of fungal cells to invade tissues, cause damage, and form biofilms. Here, we describe and characterize a novel small-molecule compound capable of inhibiting C. albicans filamentation both in vitro and in vivo; as such, this compound represents a leading candidate for the development of anti-virulence therapies against candidiasis.Jesus A. RomoChristopher G. PierceAshok K. ChaturvediAnna L. LazzellStanton F. McHardyStephen P. SavilleJose L. Lopez-RibotAmerican Society for MicrobiologyarticleCandida albicansanti-virulence factorantifungal drugsfilamentationlarge-scale phenotypic screeningMicrobiologyQR1-502ENmBio, Vol 8, Iss 6 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida albicans anti-virulence factor antifungal drugs filamentation large-scale phenotypic screening Microbiology QR1-502
spellingShingle	Candida albicans anti-virulence factor antifungal drugs filamentation large-scale phenotypic screening Microbiology QR1-502 Jesus A. Romo Christopher G. Pierce Ashok K. Chaturvedi Anna L. Lazzell Stanton F. McHardy Stephen P. Saville Jose L. Lopez-Ribot Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of <italic toggle="yes">Candida albicans</italic> Filamentation
description	ABSTRACT 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. IMPORTANCE Since fungi are eukaryotes, there is a limited number of fungus-specific targets and, as a result, the antifungal arsenal is exceedingly small. Furthermore, the efficacy of antifungal treatment is compromised by toxicity and development of resistance. As a consequence, fungal infections carry high morbidity and mortality rates, and there is an urgent but unmet need for novel antifungal agents. One appealing strategy for antifungal drug development is to target pathogenetic mechanisms associated with infection. In Candida albicans, one of the most common pathogenic fungi, morphogenetic transitions between yeast cells and filamentous hyphae represent a key virulence factor associated with the ability of fungal cells to invade tissues, cause damage, and form biofilms. Here, we describe and characterize a novel small-molecule compound capable of inhibiting C. albicans filamentation both in vitro and in vivo; as such, this compound represents a leading candidate for the development of anti-virulence therapies against candidiasis.
format	article
author	Jesus A. Romo Christopher G. Pierce Ashok K. Chaturvedi Anna L. Lazzell Stanton F. McHardy Stephen P. Saville Jose L. Lopez-Ribot
author_facet	Jesus A. Romo Christopher G. Pierce Ashok K. Chaturvedi Anna L. Lazzell Stanton F. McHardy Stephen P. Saville Jose L. Lopez-Ribot
author_sort	Jesus A. Romo
title	Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of <italic toggle="yes">Candida albicans</italic> Filamentation
title_short	Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of <italic toggle="yes">Candida albicans</italic> Filamentation
title_full	Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of <italic toggle="yes">Candida albicans</italic> Filamentation
title_fullStr	Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of <italic toggle="yes">Candida albicans</italic> Filamentation
title_full_unstemmed	Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of <italic toggle="yes">Candida albicans</italic> Filamentation
title_sort	development of anti-virulence approaches for candidiasis via a novel series of small-molecule inhibitors of <italic toggle="yes">candida albicans</italic> filamentation
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/69248be2b72a44429a21da8645afd8de
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Development of Anti-Virulence Approaches for Candidiasis via a Novel Series of Small-Molecule Inhibitors of <italic toggle="yes">Candida albicans</italic> Filamentation

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