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Screening of Pandemic Response Box Library Reveals the High Activity of Olorofim against Pathogenic Sporothrix Species

The increase in the prevalence and severity of fungal infections and the resistance to available antifungals highlights the imperative need for novel therapeutics and the search for new targets. High-content screening of libraries containing hundreds of compounds is a powerful strategy for searching...

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Autores principales: Borba-Santos, Luana Pereira, Rollin-Pinheiro, Rodrigo, da Silva Fontes, Yasmin, dos Santos, Giulia Maria Pires, de Sousa Araújo, Glauber Ribeiro, Rodrigues, Anderson Messias, Guimarães, Allan J., de Souza, Wanderley, Frases, Susana, Ferreira-Pereira, Antonio, Barreto-Bergter, Eliana, Rozental, Sonia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9605001/
https://www.ncbi.nlm.nih.gov/pubmed/36294569
http://dx.doi.org/10.3390/jof8101004
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author Borba-Santos, Luana Pereira
Rollin-Pinheiro, Rodrigo
da Silva Fontes, Yasmin
dos Santos, Giulia Maria Pires
de Sousa Araújo, Glauber Ribeiro
Rodrigues, Anderson Messias
Guimarães, Allan J.
de Souza, Wanderley
Frases, Susana
Ferreira-Pereira, Antonio
Barreto-Bergter, Eliana
Rozental, Sonia
author_facet Borba-Santos, Luana Pereira
Rollin-Pinheiro, Rodrigo
da Silva Fontes, Yasmin
dos Santos, Giulia Maria Pires
de Sousa Araújo, Glauber Ribeiro
Rodrigues, Anderson Messias
Guimarães, Allan J.
de Souza, Wanderley
Frases, Susana
Ferreira-Pereira, Antonio
Barreto-Bergter, Eliana
Rozental, Sonia
author_sort Borba-Santos, Luana Pereira
collection PubMed
description The increase in the prevalence and severity of fungal infections and the resistance to available antifungals highlights the imperative need for novel therapeutics and the search for new targets. High-content screening of libraries containing hundreds of compounds is a powerful strategy for searching for new drug candidates. In this study, we screened the Pandemic Response Box library (Medicines for Malaria Venture) of 400 diverse molecules against the Sporothrix pathogenic species. The initial screen identified twenty-four candidates that inhibited the growth of Sporothrix brasiliensis by more than 80%. Some of these compounds are known to display antifungal activity, including olorofim (MMV1782354), a new antifungal drug. Olorofim inhibited and killed the yeasts of S. brasiliensis, S. schenckii, and S. globosa at concentrations lower than itraconazole, and it also showed antibiofilm activity. According to the results obtained by fluorimetry, electron microscopy, and particle characterization analyses, we observed that olorofim induced profound alterations on the cell surface and cell cycle arrest in S. brasiliensis yeasts. We also verified that these morphophysiological alterations impaired their ability to adhere to keratinocytes in vitro. Our results indicate that olorofim is a promising new antifungal against sporotrichosis agents.
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spelling pubmed-96050012022-10-27 Screening of Pandemic Response Box Library Reveals the High Activity of Olorofim against Pathogenic Sporothrix Species Borba-Santos, Luana Pereira Rollin-Pinheiro, Rodrigo da Silva Fontes, Yasmin dos Santos, Giulia Maria Pires de Sousa Araújo, Glauber Ribeiro Rodrigues, Anderson Messias Guimarães, Allan J. de Souza, Wanderley Frases, Susana Ferreira-Pereira, Antonio Barreto-Bergter, Eliana Rozental, Sonia J Fungi (Basel) Article The increase in the prevalence and severity of fungal infections and the resistance to available antifungals highlights the imperative need for novel therapeutics and the search for new targets. High-content screening of libraries containing hundreds of compounds is a powerful strategy for searching for new drug candidates. In this study, we screened the Pandemic Response Box library (Medicines for Malaria Venture) of 400 diverse molecules against the Sporothrix pathogenic species. The initial screen identified twenty-four candidates that inhibited the growth of Sporothrix brasiliensis by more than 80%. Some of these compounds are known to display antifungal activity, including olorofim (MMV1782354), a new antifungal drug. Olorofim inhibited and killed the yeasts of S. brasiliensis, S. schenckii, and S. globosa at concentrations lower than itraconazole, and it also showed antibiofilm activity. According to the results obtained by fluorimetry, electron microscopy, and particle characterization analyses, we observed that olorofim induced profound alterations on the cell surface and cell cycle arrest in S. brasiliensis yeasts. We also verified that these morphophysiological alterations impaired their ability to adhere to keratinocytes in vitro. Our results indicate that olorofim is a promising new antifungal against sporotrichosis agents. MDPI 2022-09-25 /pmc/articles/PMC9605001/ /pubmed/36294569 http://dx.doi.org/10.3390/jof8101004 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Borba-Santos, Luana Pereira
Rollin-Pinheiro, Rodrigo
da Silva Fontes, Yasmin
dos Santos, Giulia Maria Pires
de Sousa Araújo, Glauber Ribeiro
Rodrigues, Anderson Messias
Guimarães, Allan J.
de Souza, Wanderley
Frases, Susana
Ferreira-Pereira, Antonio
Barreto-Bergter, Eliana
Rozental, Sonia
Screening of Pandemic Response Box Library Reveals the High Activity of Olorofim against Pathogenic Sporothrix Species
title Screening of Pandemic Response Box Library Reveals the High Activity of Olorofim against Pathogenic Sporothrix Species
title_full Screening of Pandemic Response Box Library Reveals the High Activity of Olorofim against Pathogenic Sporothrix Species
title_fullStr Screening of Pandemic Response Box Library Reveals the High Activity of Olorofim against Pathogenic Sporothrix Species
title_full_unstemmed Screening of Pandemic Response Box Library Reveals the High Activity of Olorofim against Pathogenic Sporothrix Species
title_short Screening of Pandemic Response Box Library Reveals the High Activity of Olorofim against Pathogenic Sporothrix Species
title_sort screening of pandemic response box library reveals the high activity of olorofim against pathogenic sporothrix species
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9605001/
https://www.ncbi.nlm.nih.gov/pubmed/36294569
http://dx.doi.org/10.3390/jof8101004
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