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Myricanol Inhibits the Type III Secretion System of Salmonella enterica Serovar Typhimurium by Interfering With the DNA-Binding Activity of HilD

The type III secretion system (T3SS) consists of a syringe-like export machine injecting effectors from the bacterial cytosol directly into host cells to establish infection. This mechanism is widely distributed in gram-negative bacteria and can be targeted as an innovative strategy for the developi...

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Autores principales: Wu, Yang, Yang, Xuefei, Zhang, Dongdong, Lu, Chunhua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546796/
https://www.ncbi.nlm.nih.gov/pubmed/33101243
http://dx.doi.org/10.3389/fmicb.2020.571217
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author Wu, Yang
Yang, Xuefei
Zhang, Dongdong
Lu, Chunhua
author_facet Wu, Yang
Yang, Xuefei
Zhang, Dongdong
Lu, Chunhua
author_sort Wu, Yang
collection PubMed
description The type III secretion system (T3SS) consists of a syringe-like export machine injecting effectors from the bacterial cytosol directly into host cells to establish infection. This mechanism is widely distributed in gram-negative bacteria and can be targeted as an innovative strategy for the developing of anti-virulence drugs. In this study, we present an effective T3SS inhibitor, myricanol, inspired by the use of folk medicinal plants traditionally used against infections. Myricanol is a cyclic diarylheptanoid isolated from the medicinal plant Myrica nagi, which is found in South and East Asia. Bioassay-guided fractionation revealed that myricanol inhibited not only the secretion of type III effector proteins of Salmonella enterica serovar Typhimurium UK-1 χ8956 (S. Typhimurium) but also the invasion of S. Typhimurium into mammalian cells, but showed no toxicity to bacterial growth or the host cells. RNA-Seq data analysis showed that the transcription of the pathogenesis-related SPI-1 gene was significantly inhibited by myricanol. Further study demonstrated that myricanol binds physically to HilD and interferes with its DNA-binding activity to the promoters of the hilA and invF genes. In conclusion, we propose that myricanol is responsible for the anti-infectious properties of M. nagi and is a novel T3SS inhibitor of S. Typhimurium through a previously unappreciated mechanism of action.
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spelling pubmed-75467962020-10-22 Myricanol Inhibits the Type III Secretion System of Salmonella enterica Serovar Typhimurium by Interfering With the DNA-Binding Activity of HilD Wu, Yang Yang, Xuefei Zhang, Dongdong Lu, Chunhua Front Microbiol Microbiology The type III secretion system (T3SS) consists of a syringe-like export machine injecting effectors from the bacterial cytosol directly into host cells to establish infection. This mechanism is widely distributed in gram-negative bacteria and can be targeted as an innovative strategy for the developing of anti-virulence drugs. In this study, we present an effective T3SS inhibitor, myricanol, inspired by the use of folk medicinal plants traditionally used against infections. Myricanol is a cyclic diarylheptanoid isolated from the medicinal plant Myrica nagi, which is found in South and East Asia. Bioassay-guided fractionation revealed that myricanol inhibited not only the secretion of type III effector proteins of Salmonella enterica serovar Typhimurium UK-1 χ8956 (S. Typhimurium) but also the invasion of S. Typhimurium into mammalian cells, but showed no toxicity to bacterial growth or the host cells. RNA-Seq data analysis showed that the transcription of the pathogenesis-related SPI-1 gene was significantly inhibited by myricanol. Further study demonstrated that myricanol binds physically to HilD and interferes with its DNA-binding activity to the promoters of the hilA and invF genes. In conclusion, we propose that myricanol is responsible for the anti-infectious properties of M. nagi and is a novel T3SS inhibitor of S. Typhimurium through a previously unappreciated mechanism of action. Frontiers Media S.A. 2020-09-25 /pmc/articles/PMC7546796/ /pubmed/33101243 http://dx.doi.org/10.3389/fmicb.2020.571217 Text en Copyright © 2020 Wu, Yang, Zhang and Lu. http://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 Microbiology
Wu, Yang
Yang, Xuefei
Zhang, Dongdong
Lu, Chunhua
Myricanol Inhibits the Type III Secretion System of Salmonella enterica Serovar Typhimurium by Interfering With the DNA-Binding Activity of HilD
title Myricanol Inhibits the Type III Secretion System of Salmonella enterica Serovar Typhimurium by Interfering With the DNA-Binding Activity of HilD
title_full Myricanol Inhibits the Type III Secretion System of Salmonella enterica Serovar Typhimurium by Interfering With the DNA-Binding Activity of HilD
title_fullStr Myricanol Inhibits the Type III Secretion System of Salmonella enterica Serovar Typhimurium by Interfering With the DNA-Binding Activity of HilD
title_full_unstemmed Myricanol Inhibits the Type III Secretion System of Salmonella enterica Serovar Typhimurium by Interfering With the DNA-Binding Activity of HilD
title_short Myricanol Inhibits the Type III Secretion System of Salmonella enterica Serovar Typhimurium by Interfering With the DNA-Binding Activity of HilD
title_sort myricanol inhibits the type iii secretion system of salmonella enterica serovar typhimurium by interfering with the dna-binding activity of hild
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546796/
https://www.ncbi.nlm.nih.gov/pubmed/33101243
http://dx.doi.org/10.3389/fmicb.2020.571217
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