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Promising Antifungal Molecules against Mucormycosis Agents Identified from Pandemic Response Box^®: In Vitro and In Silico Analyses.

ABSTRACT: Mucormycosis is considered concerning invasive fungal infections due to its high mortality rates, difficult diagnosis and limited treatment approaches. Mucorales species are highly resistant to many antifungal agents and the search for alternatives is an urgent need. In the present study, a library with 400 compounds called the Pandemic Response Box^® was used and four compounds were identified: alexidine and three non-commercial molecules. These compounds showed anti-biofilm activity, as well as alterations in fungal morphology and cell wall and plasma membrane structure. They also induced oxidative stress and mitochondrial membrane depolarization. In silico analysis revealed promising pharmacological parameters. These results suggest that these four compounds are potent candidates to be considered in future studies for the development of new approaches to treat mucormycosis.

SUBMITTER: Xisto MIDDS

PROVIDER: S-EPMC9959553 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Promising Antifungal Molecules against Mucormycosis Agents Identified from Pandemic Response Box<sup>®</sup>: In Vitro and In Silico Analyses.

Xisto Mariana Ingrid Dutra da Silva MIDDS Rollin-Pinheiro Rodrigo R de Castro-Almeida Yuri Y Dos Santos-Freitas Giulia Maria Pires GMP Rochetti Victor Pereira VP Borba-Santos Luana Pereira LP da Silva Fontes Yasmin Y Ferreira-Pereira Antonio A Rozental Sonia S Barreto-Bergter Eliana E

Journal of fungi (Basel, Switzerland) 20230131 2

Mucormycosis is considered concerning invasive fungal infections due to its high mortality rates, difficult diagnosis and limited treatment approaches. Mucorales species are highly resistant to many antifungal agents and the search for alternatives is an urgent need. In the present study, a library with 400 compounds called the Pandemic Response Box<sup>®</sup> was used and four compounds were identified: alexidine and three non-commercial molecules. These compounds showed anti-biofilm activity, ...[more]

PMID: 36836302

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Project description:Scedosporium and Lomentospora species are opportunistic filamentous fungi that cause localized and disseminated infections in immunocompetent and immunocompromised patients. These species are considered resistant fungi due to their low susceptibility to most current antifungal agents used in healthcare settings. The search for new compounds that could work as promising candidate antifungal drugs is an increasing field of interest. In this context, in the present study we screened the Pandemic Response Box® library (Medicines for Malaria Venture [MMV], Switzerland) to identify compounds with antifungal activity against Scedosporium and Lomentospora species. An initial screening of the drugs from this collection at 5 μM was performed using a clinical Scedosporium aurantiacum isolate according to the EUCAST protocol. Compounds with activity against this fungus were also tested against four other species (S. boydii¸ S. dehoogii, S. apiospermum and L. prolificans) at concentrations ranging from 0.078 to 10 μM. Seven compounds inhibited more than 80% of S. aurantiacum growth, three of them (alexidine, amorolfine and olorofim) were selected due to their differences in mechanism of action, especially when compared to drugs from the azole class. These compounds were more active against biofilm formation than against preformed biofilm in Scedosporium and Lomentospora species, except alexidine, which was able to decrease preformed biofilm about 50%. Analysis of the potential synergism of these compounds with voriconazole and caspofungin was performed by the checkerboard method for S. aurantiacum. The analysis by Bliss methodology revealed synergistic effects among selected drugs with caspofungin. When these drugs were combined with voriconazole, only alexidine and amorolfine showed a synergistic effect, whereas olorofim showed an antagonistic effect. Scanning electron microscopy revealed that alexidine induces morphology alterations in S. aurantiacum biofilm grown on a catheter surface. Reactive oxygen species production, mitochondrial activity and surface components were analyzed by fluorescent probes when S. aurantiacum was treated with selected drugs and revealed that some cell parameters are altered by these compounds. In conclusion, alexidine, amorolfine and olorofim were identified as promising compounds to be studied against scedosporiosis and lomentosporiosis.

Dataset Information

Promising Antifungal Molecules against Mucormycosis Agents Identified from Pandemic Response Box^®: In Vitro and In Silico Analyses.

Publications

Promising Antifungal Molecules against Mucormycosis Agents Identified from Pandemic Response Box<sup>®</sup>: In Vitro and In Silico Analyses.

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Dataset Information

Promising Antifungal Molecules against Mucormycosis Agents Identified from Pandemic Response Box®: In Vitro and In Silico Analyses.

Publications

Promising Antifungal Molecules against Mucormycosis Agents Identified from Pandemic Response Box<sup>®</sup>: In Vitro and In Silico Analyses.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Promising Antifungal Molecules against Mucormycosis Agents Identified from Pandemic Response Box^®: In Vitro and In Silico Analyses.