β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> via SarA-Controlled Lipoprotein-Like Cluster Expression

ABSTRACT 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...

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Autores principales:	Weilong Shang, Yifan Rao, Ying Zheng, Yi Yang, Qiwen Hu, Zhen Hu, Jizhen Yuan, Huagang Peng, Kun Xiong, Li Tan, Shu Li, Junmin Zhu, Ming Li, Xiaomei Hu, Xuhu Mao, Xiancai Rao
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	β-lactam antibiotics methicillin-resistant Staphylococcus aureus SarA TLR2 lipoprotein-like genes pathogenicity Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/eff6ce4468ec480f80be91e27f583649
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spelling	oai:doaj.org-article:eff6ce4468ec480f80be91e27f5836492021-11-15T15:55:25Zβ-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> via SarA-Controlled Lipoprotein-Like Cluster Expression10.1128/mBio.00880-192150-7511https://doaj.org/article/eff6ce4468ec480f80be91e27f5836492019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00880-19https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE β-Lactam antibiotics are widely applied to treat infectious diseases. However, certain poor disease outcomes caused by β-lactams remain poorly understood. In this study, we have identified a cluster of lipoprotein-like genes (lpl, sa2275–sa2273) that is upregulated in the major clinically prevalent MRSA clones in response to subinhibitory concentrations of β-lactam induction. The major highlight of this work is that β-lactams stimulate the expression of SarA, which directly binds to the lpl cluster promoter region and upregulates lpl expression in MRSA. Deletion of lpl significantly decreases proinflammatory cytokine levels in vitro and in vivo. The β-lactam-induced Lpls enhance host inflammatory responses by triggering the Toll-like-receptor-2-mediated expressions of interleukin-6 and tumor necrosis factor alpha. The β-lactam-induced Lpls are important virulence factors that enhance MRSA pathogenicity. These data elucidate that subinhibitory concentrations of β-lactams can exacerbate the outcomes of MRSA infection through induction of lpl controlled by the global regulator SarA.Weilong ShangYifan RaoYing ZhengYi YangQiwen HuZhen HuJizhen YuanHuagang PengKun XiongLi TanShu LiJunmin ZhuMing LiXiaomei HuXuhu MaoXiancai RaoAmerican Society for Microbiologyarticleβ-lactam antibioticsmethicillin-resistant Staphylococcus aureusSarATLR2lipoprotein-like genespathogenicityMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	β-lactam antibiotics methicillin-resistant Staphylococcus aureus SarA TLR2 lipoprotein-like genes pathogenicity Microbiology QR1-502
spellingShingle	β-lactam antibiotics methicillin-resistant Staphylococcus aureus SarA TLR2 lipoprotein-like genes pathogenicity Microbiology QR1-502 Weilong Shang Yifan Rao Ying Zheng Yi Yang Qiwen Hu Zhen Hu Jizhen Yuan Huagang Peng Kun Xiong Li Tan Shu Li Junmin Zhu Ming Li Xiaomei Hu Xuhu Mao Xiancai Rao β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> via SarA-Controlled Lipoprotein-Like Cluster Expression
description	ABSTRACT 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. IMPORTANCE β-Lactam antibiotics are widely applied to treat infectious diseases. However, certain poor disease outcomes caused by β-lactams remain poorly understood. In this study, we have identified a cluster of lipoprotein-like genes (lpl, sa2275–sa2273) that is upregulated in the major clinically prevalent MRSA clones in response to subinhibitory concentrations of β-lactam induction. The major highlight of this work is that β-lactams stimulate the expression of SarA, which directly binds to the lpl cluster promoter region and upregulates lpl expression in MRSA. Deletion of lpl significantly decreases proinflammatory cytokine levels in vitro and in vivo. The β-lactam-induced Lpls enhance host inflammatory responses by triggering the Toll-like-receptor-2-mediated expressions of interleukin-6 and tumor necrosis factor alpha. The β-lactam-induced Lpls are important virulence factors that enhance MRSA pathogenicity. These data elucidate that subinhibitory concentrations of β-lactams can exacerbate the outcomes of MRSA infection through induction of lpl controlled by the global regulator SarA.
format	article
author	Weilong Shang Yifan Rao Ying Zheng Yi Yang Qiwen Hu Zhen Hu Jizhen Yuan Huagang Peng Kun Xiong Li Tan Shu Li Junmin Zhu Ming Li Xiaomei Hu Xuhu Mao Xiancai Rao
author_facet	Weilong Shang Yifan Rao Ying Zheng Yi Yang Qiwen Hu Zhen Hu Jizhen Yuan Huagang Peng Kun Xiong Li Tan Shu Li Junmin Zhu Ming Li Xiaomei Hu Xuhu Mao Xiancai Rao
author_sort	Weilong Shang
title	β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> via SarA-Controlled Lipoprotein-Like Cluster Expression
title_short	β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> via SarA-Controlled Lipoprotein-Like Cluster Expression
title_full	β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> via SarA-Controlled Lipoprotein-Like Cluster Expression
title_fullStr	β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> via SarA-Controlled Lipoprotein-Like Cluster Expression
title_full_unstemmed	β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> via SarA-Controlled Lipoprotein-Like Cluster Expression
title_sort	β-lactam antibiotics enhance the pathogenicity of methicillin-resistant <named-content content-type="genus-species">staphylococcus aureus</named-content> via sara-controlled lipoprotein-like cluster expression
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/eff6ce4468ec480f80be91e27f583649
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β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant <named-content content-type="genus-species">Staphylococcus aureus</named-content> via SarA-Controlled Lipoprotein-Like Cluster Expression

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