文献类型： 外文期刊

作者： Yang, Xia ¹ ; Peng, Wei ¹ ; Wang, Ningning ¹ ; Dou, Beibei ¹ ; Yang, Fengming ¹ ; Chen, Huanchun ¹ ; Yuan, Fangyan ³ ; Bei, Weicheng ¹ ;

作者机构： 1.Huazhong Agr Univ, Coll Vet Med, State Key Lab Agr Microbiol, Wuhan, Peoples R China

2.Hubei Hongshan Lab, Wuhan, Peoples R China

3.Hubei Acad Agr Sci, Inst Anim Husb & Vet Sci, Key Lab Prevent & Control Agents Anim Bacteriosis, Minist Agr, Wuhan, Peoples R China

4.Huazhong Agr Univ, Cooperat Innovat Ctr Sustainable Pig Prod, Wuhan, Peoples R China

5.Guangxi Yangxiang Co Ltd, Guigang, Peoples R China

关键词： Streptococcus suis; two-component systems; fluoroquinolones; efflux pump; repressor

期刊名称：MICROBIOLOGY SPECTRUM （ 影响因子：9.043； 五年影响因子：8.113 ）

ISSN： 2165-0497

年卷期：

页码：

收录情况： SCI

摘要： Streptococcus suis is a zoonotic pathogen with high incidence and mortality rates in both swine and humans. Following antibiotic treatment, the organism has evolved many resistance mechanisms, among which efflux pump overexpression can promote drug extrusion from the cell. Streptococcus suis is an important pathogen in both pigs and humans. Although the diseases associated with S. suis can typically be treated with antibiotics, such use has resulted in a sustained increase in drug resistance. Bacteria can sense and respond to antibiotics via two-component systems (TCSs). In this study, the TCS CiaRH was identified as playing an important role in the susceptibility of S. suis to fluoroquinolones (FQs). We found that a Delta ciaRH mutant possessed lower susceptibility to FQs than the wild-type strain, with no observed growth defects at the tested concentrations and lower levels of intracellular drugs and dye. Proteomic data revealed that the levels of SatA and SatB expression were upregulated in the Delta ciaRH mutant compared with their levels in the wild-type strain. The satA and satB genes encode a narrow-spectrum FQ efflux pump. The phenomena associated with combined ciaRH-and-satAB deletion mutations almost returned the Delta ciaRH Delta satAB mutant to the phenotype of the wild-type strain compared to the phenotype of the Delta ciaRH mutant, suggesting that the resistance of the Delta ciaRH strain to FQs could be attributed to satAB overexpression. Moreover, SatAB expression was regulated by CiaR (a response regulator of CiaRH) and SatR (a regulator of the MarR family). The ciaRH genes were consistently downregulated in response to antibiotic stress. The results of electrophoretic mobility shift assays (EMSAs) and affinity assays revealed that both regulator proteins directly controlled the ABC transporter proteins SatAB. Together, the results show that cascade-mediated regulation of antibiotic export by CiaRH is crucial for the ability of S. suis to adapt to conditions of antibiotic pressure. Our study may provide a new target for future antibiotic research and development. IMPORTANCE Streptococcus suis is a zoonotic pathogen with high incidence and mortality rates in both swine and humans. Following antibiotic treatment, the organism has evolved many resistance mechanisms, among which efflux pump overexpression can promote drug extrusion from the cell. This study clarified the role of CiaRH in fluoroquinolone resistance. A mutant with the ciaRH genes deleted showed decreased susceptibility to the antibiotics tested, an invariant growth rate, and reduced intracellular efflux pump substrates. This research also demonstrated that overexpression of the efflux pump SatAB was the main cause of Delta ciaRH resistance. In addition, CiaR could combine with the promoter region of satAB to further directly suppress target gene transcription. Simultaneously, satAB was also directly regulated by SatR. Our findings may provide novel insights for the development of drug targets and help to exploit corresponding inhibitors to combat bacterial multidrug resistance.