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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2019
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.
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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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