β-Lactam Antibiotics Enhance the Pathogenicity of Methicillin-Resistant Staphylococcus aureus via SarA-Controlled Lipoprotein-Like Cluster Expression

• Published in: mBio Vol. 10; no. 3
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 11.06.2019
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - genetics; beta-Lactams - pharmacology; Female; Host-Microbe Biology; lipoprotein-like genes; Lipoproteins - genetics; methicillin-resistant Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus - drug effects; Methicillin-Resistant Staphylococcus aureus - pathogenicity; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Microbial Sensitivity Tests; Multigene Family; pathogenicity; SarA; TLR2; Toll-Like Receptor 2 - genetics; Trans-Activators - genetics; Up-Regulation; Virulence; β-lactam antibiotics; β-lactam antibiotics; pathogenicity; methicillin-resistant Staphylococcus aureus; SarA; lipoprotein-like genes; TLR2
• ISSN: 2161-2129; 2150-7511
• DOI: 10.1128/mBio.00880-19

Methicillin-resistant (MRSA) resists nearly all β-lactam antibiotics that have a bactericidal activity. However, whether the empirically used β-lactams enhance MRSA pathogenicity remains unclear. In this study, we showed that a cluster of lipoprotein-like genes ( , to [ - ]) was upregulated in MRSA in response to subinhibitory concentrations of β-lactam induction. The increasing expression of 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 deletion mutants (N315Δ and USA300Δ ) decreased the proinflammatory cytokine levels and 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 N315Δ 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 N315Δ 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. 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 ( , - ) 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 cluster promoter region and upregulates expression in MRSA. Deletion of significantly decreases proinflammatory cytokine levels and 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 controlled by the global regulator SarA.