Novel Antifungal Compounds Discovered in Medicines for Malaria Venture’s Malaria Box

ABSTRACT Similarities in fungal and animal cells make antifungal discovery efforts more difficult than those for other classes of antimicrobial drugs. Currently, there are only three major classes of antifungal drugs used for the treatment of systemic fungal diseases: polyenes, azoles, and echinocan...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Eric H. Jung, David J. Meyers, Jürgen Bosch, Arturo Casadevall
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Candida albicans Cryptococcus neoformans antifungal agents Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/06bc7255ab4847c89532a4a6c7be4859
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:06bc7255ab4847c89532a4a6c7be4859
record_format	dspace
spelling	oai:doaj.org-article:06bc7255ab4847c89532a4a6c7be48592021-11-15T15:22:14ZNovel Antifungal Compounds Discovered in Medicines for Malaria Venture’s Malaria Box10.1128/mSphere.00537-172379-5042https://doaj.org/article/06bc7255ab4847c89532a4a6c7be48592018-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00537-17https://doaj.org/toc/2379-5042ABSTRACT Similarities in fungal and animal cells make antifungal discovery efforts more difficult than those for other classes of antimicrobial drugs. Currently, there are only three major classes of antifungal drugs used for the treatment of systemic fungal diseases: polyenes, azoles, and echinocandins. Even in situations where the offending fungal organism is susceptible to the available drugs, treatment courses can be lengthy and unsatisfactory, since eradication of infection is often very difficult, especially in individuals with impaired immunity. Consequently, there is a need for new and more effective antifungal drugs. We have identified compounds with significant antifungal activity in the Malaria Box (Medicines for Malaria Ventures, Geneva, Switzerland) that have higher efficacy than some of the currently used antifungal drugs. Our best candidate, MMV665943 (IUPAC name 4-[6-[[2-(4-aminophenyl)-3H-benzimidazol-5-yl]methyl]-1H-benzimidazol-2-yl]aniline), here referred to as DM262, showed 16- to 32-fold-higher activity than fluconazole against Cryptococcus neoformans. There was also significant antifungal activity in other fungal species with known antifungal resistance, such as Lomentospora prolificans and Cryptococcus gattii. Antifungal activity was also observed against a common fungus, Candida albicans. These results are important because they offer a potentially new class of antifungal drugs and the repurposing of currently available therapeutics. IMPORTANCE Much like the recent increase in drug-resistant bacteria, there is a rise in antifungal-resistant strains of pathogenic fungi. There is a need for novel and more potent antifungal therapeutics. Consequently, we investigated a mixed library of drug-like and probe-like compounds with activity in Plasmodium spp. for activity against two common fungal pathogens, Cryptococcus neoformans and Candida albicans, along with two less common pathogenic species, Lomentospora prolificans and Cryptococcus gattii. We uncover a previously uncharacterized drug with higher broad-spectrum antifungal activity than some current treatments. Our findings may eventually lead to a compound added to the arsenal of antifungal therapeutics.Eric H. JungDavid J. MeyersJürgen BoschArturo CasadevallAmerican Society for MicrobiologyarticleCandida albicansCryptococcus neoformansantifungal agentsMicrobiologyQR1-502ENmSphere, Vol 3, Iss 2 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida albicans Cryptococcus neoformans antifungal agents Microbiology QR1-502
spellingShingle	Candida albicans Cryptococcus neoformans antifungal agents Microbiology QR1-502 Eric H. Jung David J. Meyers Jürgen Bosch Arturo Casadevall Novel Antifungal Compounds Discovered in Medicines for Malaria Venture’s Malaria Box
description	ABSTRACT Similarities in fungal and animal cells make antifungal discovery efforts more difficult than those for other classes of antimicrobial drugs. Currently, there are only three major classes of antifungal drugs used for the treatment of systemic fungal diseases: polyenes, azoles, and echinocandins. Even in situations where the offending fungal organism is susceptible to the available drugs, treatment courses can be lengthy and unsatisfactory, since eradication of infection is often very difficult, especially in individuals with impaired immunity. Consequently, there is a need for new and more effective antifungal drugs. We have identified compounds with significant antifungal activity in the Malaria Box (Medicines for Malaria Ventures, Geneva, Switzerland) that have higher efficacy than some of the currently used antifungal drugs. Our best candidate, MMV665943 (IUPAC name 4-[6-[[2-(4-aminophenyl)-3H-benzimidazol-5-yl]methyl]-1H-benzimidazol-2-yl]aniline), here referred to as DM262, showed 16- to 32-fold-higher activity than fluconazole against Cryptococcus neoformans. There was also significant antifungal activity in other fungal species with known antifungal resistance, such as Lomentospora prolificans and Cryptococcus gattii. Antifungal activity was also observed against a common fungus, Candida albicans. These results are important because they offer a potentially new class of antifungal drugs and the repurposing of currently available therapeutics. IMPORTANCE Much like the recent increase in drug-resistant bacteria, there is a rise in antifungal-resistant strains of pathogenic fungi. There is a need for novel and more potent antifungal therapeutics. Consequently, we investigated a mixed library of drug-like and probe-like compounds with activity in Plasmodium spp. for activity against two common fungal pathogens, Cryptococcus neoformans and Candida albicans, along with two less common pathogenic species, Lomentospora prolificans and Cryptococcus gattii. We uncover a previously uncharacterized drug with higher broad-spectrum antifungal activity than some current treatments. Our findings may eventually lead to a compound added to the arsenal of antifungal therapeutics.
format	article
author	Eric H. Jung David J. Meyers Jürgen Bosch Arturo Casadevall
author_facet	Eric H. Jung David J. Meyers Jürgen Bosch Arturo Casadevall
author_sort	Eric H. Jung
title	Novel Antifungal Compounds Discovered in Medicines for Malaria Venture’s Malaria Box
title_short	Novel Antifungal Compounds Discovered in Medicines for Malaria Venture’s Malaria Box
title_full	Novel Antifungal Compounds Discovered in Medicines for Malaria Venture’s Malaria Box
title_fullStr	Novel Antifungal Compounds Discovered in Medicines for Malaria Venture’s Malaria Box
title_full_unstemmed	Novel Antifungal Compounds Discovered in Medicines for Malaria Venture’s Malaria Box
title_sort	novel antifungal compounds discovered in medicines for malaria venture’s malaria box
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/06bc7255ab4847c89532a4a6c7be4859
work_keys_str_mv	AT erichjung novelantifungalcompoundsdiscoveredinmedicinesformalariaventuresmalariabox AT davidjmeyers novelantifungalcompoundsdiscoveredinmedicinesformalariaventuresmalariabox AT jurgenbosch novelantifungalcompoundsdiscoveredinmedicinesformalariaventuresmalariabox AT arturocasadevall novelantifungalcompoundsdiscoveredinmedicinesformalariaventuresmalariabox
_version_	1718428051058982912

Novel Antifungal Compounds Discovered in Medicines for Malaria Venture’s Malaria Box

Ejemplares similares