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微生物与感染  2018, Vol. 13 Issue (5): 284-298    DOI: 10.3969/j.issn.1673-6184.2018.05.005
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金黄色葡萄球菌sdhCAB操纵子影响持留菌形成机制的研究
王旭阳,陈刚,王士勇,王文婕,陈嘉臻,张文宏
复旦大学附属华山医院感染科, 上海 200040
Impact of sdhCAB operon of Staphylococcus aureus on persister formation
WANG Xuyang, CHEN Gang, WANG Shiyong, WANG Wenjie, CHEN Jiazhen, ZHANG Wenhong
Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
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摘要: 持留菌是细菌群体中的一小部分细菌,可耐受致死浓度抗生素的处理,是引起慢性感染的重要原因。金黄色葡萄球菌(Staphylococcus aureusS. aureus)作为常见致病菌,有重要临床意义。分别敲除sdhAsdhB后,金黄色葡萄球菌持留菌形成水平下降,但sdhCAB操纵子对持留菌形成的作用及机制尚不明确。本研究敲除sdh操纵子,通过酸压力、氧化压力、热压力及抗生素压力实验检测敲除株的持留菌水平,转录组测序检测敲除株的代谢通路变化,高通量微生物细胞表型检测评估敲除株的代谢水平变化。结果显示,敲除sdhCABsdhAB后,金黄色葡萄球菌对酸压力、氧化压力的耐受能力均下降;而在抗生素压力、热压力条件下,分别仅sdhCAB敲除株、sdhAB敲除株耐受能力下降。转录组测序发现,sdhCAB敲除后三羧酸循环、甲烷代谢通路及聚合酶Ⅳ等基因表达上调,耐药相关基因、氨基酸代谢基因、糖类代谢基因、卟啉代谢基因及一些转运体基因等表达下调,提示这些通路的基因参与sdhCAB影响持留菌形成的过程。此外,高通量微生物细胞表型检测发现,敲除sdhCAB可降低金黄色葡萄球菌对琥珀酸、柠檬酸、糖原、L-天冬氨酸等64种碳源的代谢。结果提示,sdhCAB操纵子对金黄色葡萄球菌持留菌形成水平有重要影响。本研究初步阐明了sdhCAB操纵子影响持留菌形成的可能机制,为研究和治疗金黄色葡萄球菌慢性感染提供了新的思路。

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王旭阳
陈刚
王士勇
王文婕
陈嘉臻
张文宏
关键词 持留菌 金黄色葡萄球菌 琥珀酸脱氢酶 转录组测序    
Abstract:Persisters are a small portion of bacteria insensitive to lethal dose of antibiotic treatment and are important cause for chronic infections. Staphylococcus aureus (S. aureus) is an important pathogen causing acute and chronic clinical infections. Although sdhCAB operon of S. aureus had been implicated in persister formation, the impact of sdhCAB operon knockout is still missing. In this study, we demonstrated that knockout of sdhCAB operon in USA500 had a significantly negative impact on its persister formation on the stress of acid, oxidation, and antibiotic treatment. The impact was reversed by gene complementation. RNA sequencing (RNA-seq) analysis showed that deletion of sdhCAB decreased the expression of genes involved in drug resistance, amino acid and carbohydrate metabolism, porphyrin metabolism, and transporters and increased the expression of genes of methane metabolism pathway, tricarboxylic acid cycle, polymerase IV, etc. Quantitative real-time polymerase chain reaction (PCR) confirmed the transcription changes in 20 out of 23 genes. Phenotype microarray analysis (PM) showed that the knockout of sdhCAB operon could decrease the metabolism of 64 carbon sources, such as succinic acid, citric acid, glycogen, and L-aspartic acid, but the metabolism of various phosphate sources and nitrogen sources was not impacted. The results suggest that the sdhCAB operon affects persister formation through its impact on metabolism. The findings provide new insights for study and treatment of S. aureus persistent infections.

Key wordsPersister    Staphylcoccus aureus    Succinate dehydrogenase    Transcriptome sequencing
基金资助:国家自然科学基金(81471987)

通讯作者: 陈嘉臻   
引用本文:   
王旭阳,陈刚,王士勇,王文婕,陈嘉臻,张文宏. 金黄色葡萄球菌sdhCAB操纵子影响持留菌形成机制的研究[J]. 微生物与感染, 2018, 13(5): 284-298.
WANG Xuyang, CHEN Gang, WANG Shiyong, WANG Wenjie, CHEN Jiazhen, ZHANG Wenhong. Impact of sdhCAB operon of Staphylococcus aureus on persister formation. JOURNAL OF MICROBES AND INFECTIONS, 2018, 13(5): 284-298.
链接本文:  
http://jmi.fudan.edu.cn/CN/10.3969/j.issn.1673-6184.2018.05.005     或     http://jmi.fudan.edu.cn/CN/Y2018/V13/I5/284

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