β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant Staphylococcus aureus via SarA-Controlled Lipoprotein-Like Cluster Expression
Methicillin-resistant Staphylococcus aureus (MRSA) resists nearly all β-lactam antibiotics that have a bactericidal activity. However, whether the empirically used β-lactams enhance MRSA pathogenicity in vivo remains unclear. In this study, we showed that a cluster of lipoprotein-like genes (lpl, sa...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561022/ https://www.ncbi.nlm.nih.gov/pubmed/31186320 http://dx.doi.org/10.1128/mBio.00880-19 |
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author | Shang, Weilong Rao, Yifan Zheng, Ying Yang, Yi Hu, Qiwen Hu, Zhen Yuan, Jizhen Peng, Huagang Xiong, Kun Tan, Li Li, Shu Zhu, Junmin Li, Ming Hu, Xiaomei Mao, Xuhu Rao, Xiancai |
author_facet | Shang, Weilong Rao, Yifan Zheng, Ying Yang, Yi Hu, Qiwen Hu, Zhen Yuan, Jizhen Peng, Huagang Xiong, Kun Tan, Li Li, Shu Zhu, Junmin Li, Ming Hu, Xiaomei Mao, Xuhu Rao, Xiancai |
author_sort | Shang, Weilong |
collection | PubMed |
description | Methicillin-resistant Staphylococcus aureus (MRSA) resists nearly all β-lactam antibiotics that have a bactericidal activity. However, whether the empirically used β-lactams enhance MRSA pathogenicity in vivo remains unclear. In this study, we showed that a cluster of lipoprotein-like genes (lpl, sa2275 to sa2273 [sa2275–sa2273]) was upregulated in MRSA in response to subinhibitory concentrations of β-lactam induction. The increasing expression of lpl by β-lactams was directly controlled by the global regulator SarA. The β-lactam-induced Lpls stimulated the production of interleukin-6 and tumor necrosis factor alpha in RAW 264.7 macrophages. The lpl deletion mutants (N315Δlpl and USA300Δlpl) decreased the proinflammatory cytokine levels in vitro and in vivo. Purified lipidated SA2275-his proteins could trigger a Toll-like-receptor-2 (TLR2)-dependent immune response in primary mouse bone marrow-derived macrophages and C57BL/6 mice. The bacterial loads of N315Δlpl in the mouse kidney were lower than those of the wild-type N315. The β-lactam-treated MRSA exacerbated cutaneous infections in both BALB/c and C57BL/6 mice, presenting increased lesion size; destroyed skin structure; and easily promoted abscess formation compared with those of the untreated MRSA. However, the size of abscesses caused by the β-lactam-treated N315 was negligibly different from those caused by the untreated N315Δlpl in C57BL/6 TLR2(−/−) mice. Our findings suggest that β-lactams must be used carefully because they might aggravate the outcome of MRSA infection compared to inaction in treatment. |
format | Online Article Text |
id | pubmed-6561022 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-65610222019-06-14 β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant Staphylococcus aureus via SarA-Controlled Lipoprotein-Like Cluster Expression Shang, Weilong Rao, Yifan Zheng, Ying Yang, Yi Hu, Qiwen Hu, Zhen Yuan, Jizhen Peng, Huagang Xiong, Kun Tan, Li Li, Shu Zhu, Junmin Li, Ming Hu, Xiaomei Mao, Xuhu Rao, Xiancai mBio Research Article Methicillin-resistant Staphylococcus aureus (MRSA) resists nearly all β-lactam antibiotics that have a bactericidal activity. However, whether the empirically used β-lactams enhance MRSA pathogenicity in vivo remains unclear. In this study, we showed that a cluster of lipoprotein-like genes (lpl, sa2275 to sa2273 [sa2275–sa2273]) was upregulated in MRSA in response to subinhibitory concentrations of β-lactam induction. The increasing expression of lpl by β-lactams was directly controlled by the global regulator SarA. The β-lactam-induced Lpls stimulated the production of interleukin-6 and tumor necrosis factor alpha in RAW 264.7 macrophages. The lpl deletion mutants (N315Δlpl and USA300Δlpl) decreased the proinflammatory cytokine levels in vitro and in vivo. Purified lipidated SA2275-his proteins could trigger a Toll-like-receptor-2 (TLR2)-dependent immune response in primary mouse bone marrow-derived macrophages and C57BL/6 mice. The bacterial loads of N315Δlpl in the mouse kidney were lower than those of the wild-type N315. The β-lactam-treated MRSA exacerbated cutaneous infections in both BALB/c and C57BL/6 mice, presenting increased lesion size; destroyed skin structure; and easily promoted abscess formation compared with those of the untreated MRSA. However, the size of abscesses caused by the β-lactam-treated N315 was negligibly different from those caused by the untreated N315Δlpl in C57BL/6 TLR2(−/−) mice. Our findings suggest that β-lactams must be used carefully because they might aggravate the outcome of MRSA infection compared to inaction in treatment. American Society for Microbiology 2019-06-11 /pmc/articles/PMC6561022/ /pubmed/31186320 http://dx.doi.org/10.1128/mBio.00880-19 Text en Copyright © 2019 Shang 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 | Research Article Shang, Weilong Rao, Yifan Zheng, Ying Yang, Yi Hu, Qiwen Hu, Zhen Yuan, Jizhen Peng, Huagang Xiong, Kun Tan, Li Li, Shu Zhu, Junmin Li, Ming Hu, Xiaomei Mao, Xuhu Rao, Xiancai β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant Staphylococcus aureus via SarA-Controlled Lipoprotein-Like Cluster Expression |
title | β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant Staphylococcus aureus via SarA-Controlled Lipoprotein-Like Cluster Expression |
title_full | β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant Staphylococcus aureus via SarA-Controlled Lipoprotein-Like Cluster Expression |
title_fullStr | β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant Staphylococcus aureus via SarA-Controlled Lipoprotein-Like Cluster Expression |
title_full_unstemmed | β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant Staphylococcus aureus via SarA-Controlled Lipoprotein-Like Cluster Expression |
title_short | β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant Staphylococcus aureus via SarA-Controlled Lipoprotein-Like Cluster Expression |
title_sort | β-lactam antibiotics enhance the pathogenicity of methicillin-resistant staphylococcus aureus via sara-controlled lipoprotein-like cluster expression |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561022/ https://www.ncbi.nlm.nih.gov/pubmed/31186320 http://dx.doi.org/10.1128/mBio.00880-19 |
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