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Antibacterial and anti-biofilm activities of histidine kinase YycG inhibitors against Streptococcus agalactiae

The Journal of Antibiotics volume 74, pages 874–883 (2021)Cite this article

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Abstract

This study aims to investigate the antibacterial and anti-biofilm activities of YycG inhibitors H2-60 and H2-81 against Streptococcus agalactiae. A total of 118 nonduplicate S. agalactiae clinical isolates were collected, and the minimal inhibitory concentrations (MICs) of H2-60 and H2-81 were determined. H2-60 and H2-81 inhibit biofilm formation of S. agalactiae were detected by crystal violet staining, and against established biofilms of S. agalactiae were observed by confocal laser scanning microscope. Inhibitory effect of H2-60 and H2-81 on the phosphorylation activity of the HisKA domain of YycG’ protein was measured. The MIC50/MIC90 was 3.13/6.25 μM for H2-60 and 6.25/12.5 μM for H2-81 against S. agalactiae, respectively. S. agalactiae planktonic cells can be decreased by H2-60 or H2-81 for more than 3 × log10 CFU ml−1 after 24 h treatment. Biofilm formation of 8 S. agalactiae strains (strong biofilm producers) was significantly reduced after treated with 1/4 × MIC of H2-60 or H2-81 for 24 h. H2-60 and H2-81 could reduce 45.79% and 29.56% of the adherent cells in the established biofilm of S. agalactiae after 72 h treatment, respectively. H2-60 combined with daptomycin reduced 83.63% of the adherent cells in the established biofilm of S. agalactiae, which was significantly better than that of H2-60 (45.79%) or daptomycin (55.07%) alone. The half maximal inhibitory concentrations (IC50) were 35.6 μM for H2-60 and 46.3 μM for H2-81 against the HisKA domain of YycG’ protein. In conclusion, YycG inhibitors H2-60 and H2-81 exhibit excellent antibacterial and anti-biofilm activities against S. agalactiae.

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Acknowledgements

The authors thank Prof Di Qu and Yang Wu (Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Science and Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University) for their suggestions and guidance. The authors also thank Dr Weiguang Pan and Jie Lian (Department of Laboratory Medicine, Huazhong University of Science and Technology Union Shenzhen Hospital), Dr Ying Wei (Department of Microbiology, the fourth Affiliated Hospital of Harbin Medical University) for helping identify and preserve the S. agalactiae strains.

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Author notes

  1. These authors contributed equally: Xiangbin Deng, Chaoqin Zhang, Junwen Chen

Authors and Affiliations

  1. Department of Infectious Diseases and the Key Lab of Endogenous Infection, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China

    Xiangbin Deng, Chaoqin Zhang, Junwen Chen, Yiyi Shi, Xiaoyu Ma, Yu Wang, Zhanwen Wang, Zhijian Yu, Jinxin Zheng & Zhong Chen

  2. Department of Infectious Diseases and the Key Lab of Endogenous Infection, Shenzhen Nanshan People’s Hospital and The 6th Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen, China

    Xiangbin Deng, Chaoqin Zhang, Junwen Chen, Yiyi Shi, Xiaoyu Ma, Yu Wang, Zhanwen Wang, Zhijian Yu, Jinxin Zheng & Zhong Chen

  3. Quality Control Center of Hospital Infection management of Shenzhen, Guang Dong Medical University, Shenzhen, China

    Zhijian Yu, Jinxin Zheng & Zhong Chen

Authors
  1. Xiangbin Deng
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Contributions

XD participated in the design of this study, collected S. agalactiae strains, biofilm assay, and drafted the paper. CZ participated in the collection of S. agalactiae strains, carried out MIC test. JC conducted time-killing assay and participated in the expression of YycG’ protein. YS and XM participated in the collection of S. agalactiae strains, MIC test and biofilm assay. YW and ZW conducted MIC test, biofilm assay and CLSM detection. ZY participated in the data analyze, and reviewed this paper. JZ and ZC designed the study, participated in the expression of YycG’ protein and conducted the inhibition of kinase activity test, conducted the data analysis, and provided critical revisions of the paper for valuable intellectual content.

Funding

This work was supported by the following grants: Sanming Project of Medicine in Shenzhen (No. SMGC201705029); Shenzhen Key Medical Discipline Construction Fund (No. SZXK06162); Natural Science Foundation of Guangdong Province, China (No. 2020A1515111146); Science, Technology and Innovation Commission of Shenzhen Municipality of key funds (JCYJ20180508162403996) and basic research funds (JCYJ20180302144345028; JCYJ20190809151817062); Shenzhen health system research project—discipline construction capacity promotion project (No. SZXJ2018027); Shenzhen Nanshan District Health Science and Technology Fund (No. 2019005).

Corresponding authors

Correspondence to Jinxin Zheng or Zhong Chen.

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The authors declare no competing interests.

Ethical approval

All procedures involving human subjects were approved by the institutional ethical committee of Huazhong University of Science and Technology Union Shenzhen Hospital and the fourth Affiliated Hospital of Harbin Medical University. Isolates were collected as part of the routine clinical management of patients, according to the national guidelines in China. Therefore, informed consent was not sought.

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Deng, X., Zhang, C., Chen, J. et al. Antibacterial and anti-biofilm activities of histidine kinase YycG inhibitors against Streptococcus agalactiae. J Antibiot 74, 874–883 (2021). https://doi.org/10.1038/s41429-021-00475-6

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