New Organic Compounds Against Scedosporium and Mucorales: Antifungal Activity and Mechanisms of Cell Wall and Membrane Disruption
4 affiliations
- 1Departamento de Microbiologia, Imunologia e Parasitologia, Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro 20550-170, Brazil
- 2Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil
- 3Laboratório de Biologia Estrutural, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro 21040-900, Brazil
- 4Department of Fundamental Chemistry, Institute of Chemistry, University of São Paulo, São Paulo 05508-000, Brazil
Abstract
The emergence of infections caused by Scedosporium/Lomentospora and Mucorales species poses a major clinical challenge due to their intrinsic resistance to multiple antifungal drugs and the limited number of therapeutic options available. In this study, we evaluated the antifungal activity of synthetic organic compounds and characterized the mechanisms of antifungal activity. Eight compounds were initially screened against Scedosporium aurantiacum and Rhizopus oryzae. Compounds 2, 3, and 4 inhibited more than 60% of fungal growth and were selected for further characterization. Antifungal susceptibility assays revealed that compound 2 exhibited the strongest activity, with minimum inhibitory concentrations ranging from 12.5 to 25 μg/mL, whereas compounds 3 and 4 showed MIC values between 50 and 100 μg/mL. All compounds displayed fungistatic activity and significantly impaired fungal germination and biofilm development. Drug interaction analyses demonstrated additive or synergistic effects when the compounds were combined with clinically used antifungals. Investigations revealed that the compounds induced alterations in the fungal cell surface, including reductions in neutral lipids and chitin, increased membrane permeability, disruption of sterol-enriched membrane microdomains, and ultrastructural abnormalities. Exogenous ergosterol partially reversed the activity of compounds 2 and 3, suggesting interactions with membrane sterols. In silico toxicity prediction indicated generally favorable safety profiles. In summary, these findings identify synthetic organic compounds as promising scaffolds for antifungal drug discovery and highlight their potential to target fungal membrane and cell wall integrity in resistant filamentous pathogens.
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BibTeX
@article{rollinpinheiro2026organic,
title = {{New Organic Compounds Against Scedosporium and Mucorales: Antifungal Activity and Mechanisms of Cell Wall and Membrane Disruption}},
author = {Rodrigo Rollin-Pinheiro and Yuri de Castro-Almeida and Mariana Ingrid Dutra da Silva Xisto and Johnatha de Souza-Santos and Daniel Clemente de Moraes and Bruno Vicente and Victor Midlej and Fabiano Travanca Toledo and Renan Ferrarini and Glaucio Monteiro Ferreira and Alcindo A. Dos Santos and Eliana Barreto-Bergter and Antonio Ferreira-Pereira},
journal = {Molecules},
year = {2026},
month = oct,
doi = {10.3390/molecules31203691},
url = {https://www.mdpi.com/1420-3049/31/20/3691},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - New Organic Compounds Against Scedosporium and Mucorales: Antifungal Activity and Mechanisms of Cell Wall and Membrane Disruption
AU - Rodrigo Rollin-Pinheiro
AU - Yuri de Castro-Almeida
AU - Mariana Ingrid Dutra da Silva Xisto
AU - Johnatha de Souza-Santos
AU - Daniel Clemente de Moraes
AU - Bruno Vicente
AU - Victor Midlej
AU - Fabiano Travanca Toledo
AU - Renan Ferrarini
AU - Glaucio Monteiro Ferreira
AU - Alcindo A. Dos Santos
AU - Eliana Barreto-Bergter
AU - Antonio Ferreira-Pereira
PY - 2026
DA - 2026/10/01
JO - Molecules
DO - 10.3390/molecules31203691
UR - https://www.mdpi.com/1420-3049/31/20/3691
AB - The emergence of infections caused by Scedosporium/Lomentospora and Mucorales species poses a major clinical challenge due to their intrinsic resistance to multiple antifungal drugs and the limited number of therapeutic options available. In this study, we evaluated the antifungal activity of synthetic organic compounds and characterized the mechanisms of antifungal activity. Eight compounds were initially screened against Scedosporium aurantiacum and Rhizopus oryzae. Compounds 2, 3, and 4 inhibited more than 60% of fungal growth and were selected for further characterization. Antifungal susceptibility assays revealed that compound 2 exhibited the strongest activity, with minimum inhibitory concentrations ranging from 12.5 to 25 μg/mL, whereas compounds 3 and 4 showed MIC values between 50 and 100 μg/mL. All compounds displayed fungistatic activity and significantly impaired fungal germination and biofilm development. Drug interaction analyses demonstrated additive or synergistic effects when the compounds were combined with clinically used antifungals. Investigations revealed that the compounds induced alterations in the fungal cell surface, including reductions in neutral lipids and chitin, increased membrane permeability, disruption of sterol-enriched membrane microdomains, and ultrastructural abnormalities. Exogenous ergosterol partially reversed the activity of compounds 2 and 3, suggesting interactions with membrane sterols. In silico toxicity prediction indicated generally favorable safety profiles. In summary, these findings identify synthetic organic compounds as promising scaffolds for antifungal drug discovery and highlight their potential to target fungal membrane and cell wall integrity in resistant filamentous pathogens.
SN - 1420-3049
ER -