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Antifungal Effect of All-trans Retinoic Acid against Aspergillus fumigatus In Vitro and in a Pulmonary Aspergillosis In Vivo Model

Aspergillus fumigatus is the most common opportunistic fungal pathogen and causes invasive pulmonary aspergillosis (IPA), with high mortality among immunosuppressed patients. The fungistatic activity of all-trans retinoic acid (ATRA) has been recently described in vitro. We evaluated the efficacy of...

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Autores principales: Campione, Elena, Gaziano, Roberta, Doldo, Elena, Marino, Daniele, Falconi, Mattia, Iacovelli, Federico, Tagliaferri, Daniela, Pacello, Lucrezia, Bianchi, Luca, Lanna, Caterina, Aurisicchio, Luigi, Centofanti, Federica, Di Francesco, Paolo, Del Principe, Ilaria, Del Bufalo, Francesca, Locatelli, Franco, Pistoia, Enrico Salvatore, Marra, Emanuele, Orlandi, Augusto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092556/
https://www.ncbi.nlm.nih.gov/pubmed/33361288
http://dx.doi.org/10.1128/AAC.01874-20
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author Campione, Elena
Gaziano, Roberta
Doldo, Elena
Marino, Daniele
Falconi, Mattia
Iacovelli, Federico
Tagliaferri, Daniela
Pacello, Lucrezia
Bianchi, Luca
Lanna, Caterina
Aurisicchio, Luigi
Centofanti, Federica
Di Francesco, Paolo
Del Principe, Ilaria
Del Bufalo, Francesca
Locatelli, Franco
Pistoia, Enrico Salvatore
Marra, Emanuele
Orlandi, Augusto
author_facet Campione, Elena
Gaziano, Roberta
Doldo, Elena
Marino, Daniele
Falconi, Mattia
Iacovelli, Federico
Tagliaferri, Daniela
Pacello, Lucrezia
Bianchi, Luca
Lanna, Caterina
Aurisicchio, Luigi
Centofanti, Federica
Di Francesco, Paolo
Del Principe, Ilaria
Del Bufalo, Francesca
Locatelli, Franco
Pistoia, Enrico Salvatore
Marra, Emanuele
Orlandi, Augusto
author_sort Campione, Elena
collection PubMed
description Aspergillus fumigatus is the most common opportunistic fungal pathogen and causes invasive pulmonary aspergillosis (IPA), with high mortality among immunosuppressed patients. The fungistatic activity of all-trans retinoic acid (ATRA) has been recently described in vitro. We evaluated the efficacy of ATRA in vivo and its potential synergistic interaction with other antifungal drugs. A rat model of IPA and in vitro experiments were performed to assess the efficacy of ATRA against Aspergillus in association with classical antifungal drugs and in silico studies used to clarify its mechanism of action. ATRA (0.5 and 1 mM) displayed a strong fungistatic activity in Aspergillus cultures, while at lower concentrations, synergistically potentiated fungistatic efficacy of subinhibitory concentration of amphotericin B (AmB) and posaconazole (POS). ATRA also enhanced macrophagic phagocytosis of conidia. In a rat model of IPA, ATRA reduced mortality similarly to posaconazole. Fungistatic efficacy of ATRA alone and synergistically with other antifungal drugs was documented in vitro, likely by inhibiting fungal heat shock protein 90 (Hsp90) expression and Hsp90-related genes. ATRA treatment reduced mortality in a model of IPA in vivo. Those findings suggest ATRA as a suitable fungistatic agent that can also reduce dosage and adverse reactions of classical antifungal drugs and add to the development of new therapeutic strategies against IPA and systemic fungal infections.
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spelling pubmed-80925562021-05-05 Antifungal Effect of All-trans Retinoic Acid against Aspergillus fumigatus In Vitro and in a Pulmonary Aspergillosis In Vivo Model Campione, Elena Gaziano, Roberta Doldo, Elena Marino, Daniele Falconi, Mattia Iacovelli, Federico Tagliaferri, Daniela Pacello, Lucrezia Bianchi, Luca Lanna, Caterina Aurisicchio, Luigi Centofanti, Federica Di Francesco, Paolo Del Principe, Ilaria Del Bufalo, Francesca Locatelli, Franco Pistoia, Enrico Salvatore Marra, Emanuele Orlandi, Augusto Antimicrob Agents Chemother Experimental Therapeutics Aspergillus fumigatus is the most common opportunistic fungal pathogen and causes invasive pulmonary aspergillosis (IPA), with high mortality among immunosuppressed patients. The fungistatic activity of all-trans retinoic acid (ATRA) has been recently described in vitro. We evaluated the efficacy of ATRA in vivo and its potential synergistic interaction with other antifungal drugs. A rat model of IPA and in vitro experiments were performed to assess the efficacy of ATRA against Aspergillus in association with classical antifungal drugs and in silico studies used to clarify its mechanism of action. ATRA (0.5 and 1 mM) displayed a strong fungistatic activity in Aspergillus cultures, while at lower concentrations, synergistically potentiated fungistatic efficacy of subinhibitory concentration of amphotericin B (AmB) and posaconazole (POS). ATRA also enhanced macrophagic phagocytosis of conidia. In a rat model of IPA, ATRA reduced mortality similarly to posaconazole. Fungistatic efficacy of ATRA alone and synergistically with other antifungal drugs was documented in vitro, likely by inhibiting fungal heat shock protein 90 (Hsp90) expression and Hsp90-related genes. ATRA treatment reduced mortality in a model of IPA in vivo. Those findings suggest ATRA as a suitable fungistatic agent that can also reduce dosage and adverse reactions of classical antifungal drugs and add to the development of new therapeutic strategies against IPA and systemic fungal infections. American Society for Microbiology 2021-02-17 /pmc/articles/PMC8092556/ /pubmed/33361288 http://dx.doi.org/10.1128/AAC.01874-20 Text en Copyright © 2021 Campione et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Experimental Therapeutics
Campione, Elena
Gaziano, Roberta
Doldo, Elena
Marino, Daniele
Falconi, Mattia
Iacovelli, Federico
Tagliaferri, Daniela
Pacello, Lucrezia
Bianchi, Luca
Lanna, Caterina
Aurisicchio, Luigi
Centofanti, Federica
Di Francesco, Paolo
Del Principe, Ilaria
Del Bufalo, Francesca
Locatelli, Franco
Pistoia, Enrico Salvatore
Marra, Emanuele
Orlandi, Augusto
Antifungal Effect of All-trans Retinoic Acid against Aspergillus fumigatus In Vitro and in a Pulmonary Aspergillosis In Vivo Model
title Antifungal Effect of All-trans Retinoic Acid against Aspergillus fumigatus In Vitro and in a Pulmonary Aspergillosis In Vivo Model
title_full Antifungal Effect of All-trans Retinoic Acid against Aspergillus fumigatus In Vitro and in a Pulmonary Aspergillosis In Vivo Model
title_fullStr Antifungal Effect of All-trans Retinoic Acid against Aspergillus fumigatus In Vitro and in a Pulmonary Aspergillosis In Vivo Model
title_full_unstemmed Antifungal Effect of All-trans Retinoic Acid against Aspergillus fumigatus In Vitro and in a Pulmonary Aspergillosis In Vivo Model
title_short Antifungal Effect of All-trans Retinoic Acid against Aspergillus fumigatus In Vitro and in a Pulmonary Aspergillosis In Vivo Model
title_sort antifungal effect of all-trans retinoic acid against aspergillus fumigatus in vitro and in a pulmonary aspergillosis in vivo model
topic Experimental Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092556/
https://www.ncbi.nlm.nih.gov/pubmed/33361288
http://dx.doi.org/10.1128/AAC.01874-20
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