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Oroxylin A Inhibits Hemolysis via Hindering the Self-Assembly of α-Hemolysin Heptameric Transmembrane Pore
Alpha-hemolysin (α-HL) is a self-assembling, channel-forming toxin produced by most Staphylococcus aureus strains as a 33.2-kDa soluble monomer. Upon binding to a susceptible cell membrane, the monomer self-assembles to form a 232.4-kDa heptamer that ultimately causes host cell lysis and death. Cons...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547825/ https://www.ncbi.nlm.nih.gov/pubmed/23349625 http://dx.doi.org/10.1371/journal.pcbi.1002869 |
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author | Dong, Jing Qiu, Jiazhang Zhang, Yu Lu, Chongjian Dai, Xiaohan Wang, Jianfeng Li, Hongen Wang, Xin Tan, Wei Luo, Mingjing Niu, Xiaodi Deng, Xuming |
author_facet | Dong, Jing Qiu, Jiazhang Zhang, Yu Lu, Chongjian Dai, Xiaohan Wang, Jianfeng Li, Hongen Wang, Xin Tan, Wei Luo, Mingjing Niu, Xiaodi Deng, Xuming |
author_sort | Dong, Jing |
collection | PubMed |
description | Alpha-hemolysin (α-HL) is a self-assembling, channel-forming toxin produced by most Staphylococcus aureus strains as a 33.2-kDa soluble monomer. Upon binding to a susceptible cell membrane, the monomer self-assembles to form a 232.4-kDa heptamer that ultimately causes host cell lysis and death. Consequently, α-HL plays a significant role in the pathogenesis of S. aureus infections, such as pneumonia, mastitis, keratitis and arthritis. In this paper, experimental studies show that oroxylin A (ORO), a natural compound without anti-S. aureus activity, can inhibit the hemolytic activity of α-HL. Molecular dynamics simulations, free energy calculations, and mutagenesis assays were performed to understand the formation of the α-HL-ORO complex. This combined approach revealed that the catalytic mechanism of inhibition involves the direct binding of ORO to α-HL, which blocks the conformational transition of the critical “Loop” region of the α-HL protein thereby inhibiting its hemolytic activity. This mechanism was confirmed by experimental data obtained from a deoxycholate-induced oligomerization assay. It was also found that, in a co-culture system with S. aureus and human alveolar epithelial (A549) cells, ORO could protect against α-HL-mediated injury. These findings indicate that ORO hinders the lytic activity of α-HL through a novel mechanism, which should facilitate the design of new and more effective antibacterial agents against S. aureus. |
format | Online Article Text |
id | pubmed-3547825 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-35478252013-01-24 Oroxylin A Inhibits Hemolysis via Hindering the Self-Assembly of α-Hemolysin Heptameric Transmembrane Pore Dong, Jing Qiu, Jiazhang Zhang, Yu Lu, Chongjian Dai, Xiaohan Wang, Jianfeng Li, Hongen Wang, Xin Tan, Wei Luo, Mingjing Niu, Xiaodi Deng, Xuming PLoS Comput Biol Research Article Alpha-hemolysin (α-HL) is a self-assembling, channel-forming toxin produced by most Staphylococcus aureus strains as a 33.2-kDa soluble monomer. Upon binding to a susceptible cell membrane, the monomer self-assembles to form a 232.4-kDa heptamer that ultimately causes host cell lysis and death. Consequently, α-HL plays a significant role in the pathogenesis of S. aureus infections, such as pneumonia, mastitis, keratitis and arthritis. In this paper, experimental studies show that oroxylin A (ORO), a natural compound without anti-S. aureus activity, can inhibit the hemolytic activity of α-HL. Molecular dynamics simulations, free energy calculations, and mutagenesis assays were performed to understand the formation of the α-HL-ORO complex. This combined approach revealed that the catalytic mechanism of inhibition involves the direct binding of ORO to α-HL, which blocks the conformational transition of the critical “Loop” region of the α-HL protein thereby inhibiting its hemolytic activity. This mechanism was confirmed by experimental data obtained from a deoxycholate-induced oligomerization assay. It was also found that, in a co-culture system with S. aureus and human alveolar epithelial (A549) cells, ORO could protect against α-HL-mediated injury. These findings indicate that ORO hinders the lytic activity of α-HL through a novel mechanism, which should facilitate the design of new and more effective antibacterial agents against S. aureus. Public Library of Science 2013-01-17 /pmc/articles/PMC3547825/ /pubmed/23349625 http://dx.doi.org/10.1371/journal.pcbi.1002869 Text en © 2013 Dong et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Dong, Jing Qiu, Jiazhang Zhang, Yu Lu, Chongjian Dai, Xiaohan Wang, Jianfeng Li, Hongen Wang, Xin Tan, Wei Luo, Mingjing Niu, Xiaodi Deng, Xuming Oroxylin A Inhibits Hemolysis via Hindering the Self-Assembly of α-Hemolysin Heptameric Transmembrane Pore |
title | Oroxylin A Inhibits Hemolysis via Hindering the Self-Assembly of α-Hemolysin Heptameric Transmembrane Pore |
title_full | Oroxylin A Inhibits Hemolysis via Hindering the Self-Assembly of α-Hemolysin Heptameric Transmembrane Pore |
title_fullStr | Oroxylin A Inhibits Hemolysis via Hindering the Self-Assembly of α-Hemolysin Heptameric Transmembrane Pore |
title_full_unstemmed | Oroxylin A Inhibits Hemolysis via Hindering the Self-Assembly of α-Hemolysin Heptameric Transmembrane Pore |
title_short | Oroxylin A Inhibits Hemolysis via Hindering the Self-Assembly of α-Hemolysin Heptameric Transmembrane Pore |
title_sort | oroxylin a inhibits hemolysis via hindering the self-assembly of α-hemolysin heptameric transmembrane pore |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547825/ https://www.ncbi.nlm.nih.gov/pubmed/23349625 http://dx.doi.org/10.1371/journal.pcbi.1002869 |
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