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Succinylation modification provides new insights for the treatment of immunocompromised individuals with drug-resistant Aspergillus fumigatus infection

Invasive Aspergillus fumigatus infection poses a serious threat to global human health, especially to immunocompromised individuals. Currently, triazole drugs are the most commonly used antifungals for aspergillosis. However, owing to the emergence of drug-resistant strains, the effect of triazole d...

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Autores principales: Chen, Xianzhen, Lei, Wenzhi, Meng, Hui, Jiang, Yi, Zhang, Sanli, Chen, Huyan, Du, Mingwei, Xue, Xiaochun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150703/
https://www.ncbi.nlm.nih.gov/pubmed/37138872
http://dx.doi.org/10.3389/fimmu.2023.1161642
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author Chen, Xianzhen
Lei, Wenzhi
Meng, Hui
Jiang, Yi
Zhang, Sanli
Chen, Huyan
Du, Mingwei
Xue, Xiaochun
author_facet Chen, Xianzhen
Lei, Wenzhi
Meng, Hui
Jiang, Yi
Zhang, Sanli
Chen, Huyan
Du, Mingwei
Xue, Xiaochun
author_sort Chen, Xianzhen
collection PubMed
description Invasive Aspergillus fumigatus infection poses a serious threat to global human health, especially to immunocompromised individuals. Currently, triazole drugs are the most commonly used antifungals for aspergillosis. However, owing to the emergence of drug-resistant strains, the effect of triazole drugs is greatly restricted, resulting in a mortality rate as high as 80%. Succinylation, a novel post-translational modification, is attracting increasing interest, although its biological function in triazole resistance remains unclear. In this study, we initiated the screening of lysine succinylation in A. fumigatus. We discovered that some of the succinylation sites differed significantly among strains with unequal itraconazole (ITR) resistance. Bioinformatics analysis showed that the succinylated proteins are involved in a broad range of cellular functions with diverse subcellular localizations, the most notable of which is cell metabolism. Further antifungal sensitivity tests confirmed the synergistic fungicidal effects of dessuccinylase inhibitor nicotinamide (NAM) on ITR-resistant A. fumigatus. In vivo experiments revealed that treatment with NAM alone or in combination with ITR significantly increased the survival of neutropenic mice infected with A. fumigatus. In vitro experiments showed that NAM enhanced the killing effect of THP-1 macrophages on A. fumigatus conidia. Our results suggest that lysine succinylation plays an indispensable role in ITR resistance of A. fumigatus. Dessuccinylase inhibitor NAM alone or in combination with ITR exerted good effects against A. fumigatus infection in terms of synergistic fungicidal effect and enhancing macrophage killing effect. These results provide mechanistic insights that will aid in the treatment of ITR-resistant fungal infections.
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spelling pubmed-101507032023-05-02 Succinylation modification provides new insights for the treatment of immunocompromised individuals with drug-resistant Aspergillus fumigatus infection Chen, Xianzhen Lei, Wenzhi Meng, Hui Jiang, Yi Zhang, Sanli Chen, Huyan Du, Mingwei Xue, Xiaochun Front Immunol Immunology Invasive Aspergillus fumigatus infection poses a serious threat to global human health, especially to immunocompromised individuals. Currently, triazole drugs are the most commonly used antifungals for aspergillosis. However, owing to the emergence of drug-resistant strains, the effect of triazole drugs is greatly restricted, resulting in a mortality rate as high as 80%. Succinylation, a novel post-translational modification, is attracting increasing interest, although its biological function in triazole resistance remains unclear. In this study, we initiated the screening of lysine succinylation in A. fumigatus. We discovered that some of the succinylation sites differed significantly among strains with unequal itraconazole (ITR) resistance. Bioinformatics analysis showed that the succinylated proteins are involved in a broad range of cellular functions with diverse subcellular localizations, the most notable of which is cell metabolism. Further antifungal sensitivity tests confirmed the synergistic fungicidal effects of dessuccinylase inhibitor nicotinamide (NAM) on ITR-resistant A. fumigatus. In vivo experiments revealed that treatment with NAM alone or in combination with ITR significantly increased the survival of neutropenic mice infected with A. fumigatus. In vitro experiments showed that NAM enhanced the killing effect of THP-1 macrophages on A. fumigatus conidia. Our results suggest that lysine succinylation plays an indispensable role in ITR resistance of A. fumigatus. Dessuccinylase inhibitor NAM alone or in combination with ITR exerted good effects against A. fumigatus infection in terms of synergistic fungicidal effect and enhancing macrophage killing effect. These results provide mechanistic insights that will aid in the treatment of ITR-resistant fungal infections. Frontiers Media S.A. 2023-04-17 /pmc/articles/PMC10150703/ /pubmed/37138872 http://dx.doi.org/10.3389/fimmu.2023.1161642 Text en Copyright © 2023 Chen, Lei, Meng, Jiang, Zhang, Chen, Du and Xue https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Chen, Xianzhen
Lei, Wenzhi
Meng, Hui
Jiang, Yi
Zhang, Sanli
Chen, Huyan
Du, Mingwei
Xue, Xiaochun
Succinylation modification provides new insights for the treatment of immunocompromised individuals with drug-resistant Aspergillus fumigatus infection
title Succinylation modification provides new insights for the treatment of immunocompromised individuals with drug-resistant Aspergillus fumigatus infection
title_full Succinylation modification provides new insights for the treatment of immunocompromised individuals with drug-resistant Aspergillus fumigatus infection
title_fullStr Succinylation modification provides new insights for the treatment of immunocompromised individuals with drug-resistant Aspergillus fumigatus infection
title_full_unstemmed Succinylation modification provides new insights for the treatment of immunocompromised individuals with drug-resistant Aspergillus fumigatus infection
title_short Succinylation modification provides new insights for the treatment of immunocompromised individuals with drug-resistant Aspergillus fumigatus infection
title_sort succinylation modification provides new insights for the treatment of immunocompromised individuals with drug-resistant aspergillus fumigatus infection
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150703/
https://www.ncbi.nlm.nih.gov/pubmed/37138872
http://dx.doi.org/10.3389/fimmu.2023.1161642
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