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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...

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Autores principales: Dong, Jing, Qiu, Jiazhang, Zhang, Yu, Lu, Chongjian, Dai, Xiaohan, Wang, Jianfeng, Li, Hongen, Wang, Xin, Tan, Wei, Luo, Mingjing, Niu, Xiaodi, Deng, Xuming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
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.
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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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