Alexidine Dihydrochloride Has Broad-Spectrum Activities against Diverse Fungal Pathogens

ABSTRACT Invasive fungal infections due to Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans constitute a substantial threat to hospitalized immunocompromised patients. Further, the presence of drug-recalcitrant biofilms on medical devices and emergence of drug-resistant fungi, su...

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Autores principales:	Zeinab Mamouei, Abdullah Alqarihi, Shakti Singh, Shuying Xu, Michael K. Mansour, Ashraf S. Ibrahim, Priya Uppuluri
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Candida albicans FDA HTS antifungal agents biofilms panfungal Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/583d18daac1441dca9cc718873a9ba59
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spelling	oai:doaj.org-article:583d18daac1441dca9cc718873a9ba592021-11-15T15:22:26ZAlexidine Dihydrochloride Has Broad-Spectrum Activities against Diverse Fungal Pathogens10.1128/mSphere.00539-182379-5042https://doaj.org/article/583d18daac1441dca9cc718873a9ba592018-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00539-18https://doaj.org/toc/2379-5042ABSTRACT Invasive fungal infections due to Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans constitute a substantial threat to hospitalized immunocompromised patients. Further, the presence of drug-recalcitrant biofilms on medical devices and emergence of drug-resistant fungi, such as Candida auris, introduce treatment challenges with current antifungal drugs. Worse, currently there is no approved drug capable of obviating preformed biofilms, which increase the chance of infection relapses. Here, we screened a small-molecule New Prestwick Chemical Library, consisting of 1,200 FDA-approved off-patent drugs against C. albicans, C. auris, and A. fumigatus, to identify those that inhibit growth of all three pathogens. Inhibitors were further prioritized for their potency against other fungal pathogens and their ability to kill preformed biofilms. Our studies identified the bis-biguanide alexidine dihydrochloride (AXD) as a drug with the highest antifungal and antibiofilm activity against a diverse range of fungal pathogens. Finally, AXD significantly potentiated the efficacy of fluconazole against biofilms, displayed low mammalian cell toxicity, and eradicated biofilms growing in mouse central venous catheters in vivo, highlighting its potential as a pan-antifungal drug. IMPORTANCE The prevalence of fungal infections has seen a rise in the past decades due to advances in modern medicine leading to an expanding population of device-associated and immunocompromised patients. Furthermore, the spectrum of pathogenic fungi has changed, with the emergence of multidrug-resistant strains such as C. auris. High mortality related to fungal infections points to major limitations of current antifungal therapy and an unmet need for new antifungal drugs. We screened a library of repurposed FDA-approved inhibitors to identify compounds with activities against a diverse range of fungi in varied phases of growth. The assays identified alexidine dihydrochloride (AXD) to have pronounced antifungal activity, including against preformed biofilms, at concentrations lower than mammalian cell toxicity. AXD potentiated the activity of fluconazole and amphotericin B against Candida biofilms in vitro and prevented biofilm growth in vivo. Thus, AXD has the potential to be developed as a pan-antifungal, antibiofilm drug.Zeinab MamoueiAbdullah AlqarihiShakti SinghShuying XuMichael K. MansourAshraf S. IbrahimPriya UppuluriAmerican Society for MicrobiologyarticleCandida albicansFDAHTSantifungal agentsbiofilmspanfungalMicrobiologyQR1-502ENmSphere, Vol 3, Iss 5 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida albicans FDA HTS antifungal agents biofilms panfungal Microbiology QR1-502
spellingShingle	Candida albicans FDA HTS antifungal agents biofilms panfungal Microbiology QR1-502 Zeinab Mamouei Abdullah Alqarihi Shakti Singh Shuying Xu Michael K. Mansour Ashraf S. Ibrahim Priya Uppuluri Alexidine Dihydrochloride Has Broad-Spectrum Activities against Diverse Fungal Pathogens
description	ABSTRACT Invasive fungal infections due to Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans constitute a substantial threat to hospitalized immunocompromised patients. Further, the presence of drug-recalcitrant biofilms on medical devices and emergence of drug-resistant fungi, such as Candida auris, introduce treatment challenges with current antifungal drugs. Worse, currently there is no approved drug capable of obviating preformed biofilms, which increase the chance of infection relapses. Here, we screened a small-molecule New Prestwick Chemical Library, consisting of 1,200 FDA-approved off-patent drugs against C. albicans, C. auris, and A. fumigatus, to identify those that inhibit growth of all three pathogens. Inhibitors were further prioritized for their potency against other fungal pathogens and their ability to kill preformed biofilms. Our studies identified the bis-biguanide alexidine dihydrochloride (AXD) as a drug with the highest antifungal and antibiofilm activity against a diverse range of fungal pathogens. Finally, AXD significantly potentiated the efficacy of fluconazole against biofilms, displayed low mammalian cell toxicity, and eradicated biofilms growing in mouse central venous catheters in vivo, highlighting its potential as a pan-antifungal drug. IMPORTANCE The prevalence of fungal infections has seen a rise in the past decades due to advances in modern medicine leading to an expanding population of device-associated and immunocompromised patients. Furthermore, the spectrum of pathogenic fungi has changed, with the emergence of multidrug-resistant strains such as C. auris. High mortality related to fungal infections points to major limitations of current antifungal therapy and an unmet need for new antifungal drugs. We screened a library of repurposed FDA-approved inhibitors to identify compounds with activities against a diverse range of fungi in varied phases of growth. The assays identified alexidine dihydrochloride (AXD) to have pronounced antifungal activity, including against preformed biofilms, at concentrations lower than mammalian cell toxicity. AXD potentiated the activity of fluconazole and amphotericin B against Candida biofilms in vitro and prevented biofilm growth in vivo. Thus, AXD has the potential to be developed as a pan-antifungal, antibiofilm drug.
format	article
author	Zeinab Mamouei Abdullah Alqarihi Shakti Singh Shuying Xu Michael K. Mansour Ashraf S. Ibrahim Priya Uppuluri
author_facet	Zeinab Mamouei Abdullah Alqarihi Shakti Singh Shuying Xu Michael K. Mansour Ashraf S. Ibrahim Priya Uppuluri
author_sort	Zeinab Mamouei
title	Alexidine Dihydrochloride Has Broad-Spectrum Activities against Diverse Fungal Pathogens
title_short	Alexidine Dihydrochloride Has Broad-Spectrum Activities against Diverse Fungal Pathogens
title_full	Alexidine Dihydrochloride Has Broad-Spectrum Activities against Diverse Fungal Pathogens
title_fullStr	Alexidine Dihydrochloride Has Broad-Spectrum Activities against Diverse Fungal Pathogens
title_full_unstemmed	Alexidine Dihydrochloride Has Broad-Spectrum Activities against Diverse Fungal Pathogens
title_sort	alexidine dihydrochloride has broad-spectrum activities against diverse fungal pathogens
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/583d18daac1441dca9cc718873a9ba59
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Alexidine Dihydrochloride Has Broad-Spectrum Activities against Diverse Fungal Pathogens

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