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Inhibition of Staphylococcus aureus and biofilm formation by the anthelminthic drug, triclabendazole

The Journal of Antibiotics volume 75, pages 287–295 (2022)Cite this article

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Abstract

Triclabendazole (TBD) has been widely used in the treatment of helminthic infection. The anti-biofilm activity and antibacterial mechanism of TBD against Staphylococcus aureus were not known. Here, the anti-biofilm activity of TBD against clinical S. aureus isolates from China was systematically evaluated. Under TBD pressure, TBD-induced tolerant S. aureus with elevated TBD minimum inhibitory concentration (MIC) was selected in vitro and the genetic mutations between the parental isolates and TBD-induced tolerant derivatives were determined by whole-genome sequencing. TBD could significantly inhibit biofilm formation at sub-inhibitory concentration and disperse mature biofilm of clinical S. aureus isolates. In addition, TBD displayed bactericidal activity against the bacterial cells embedded in the biofilm and showed anti-persisters activity. Proteomic analysis showed that KEGG pathways of ABC transporters and beta-lactam resistance were significantly changed after TBD exposure. Moreover, SAUSA300_RS08395 (molecular chaperone DnaK), SAUSA300_RS11200 (sensor histidine kinase KdpD), SAUSA300_RS06325 (DNA translocase FtsK) were identified as candidate targets of TBD in S. aureus. Overexpression experiments further demonstrated that the elevated transcriptional level of DnaK resulted in S. aureus growth delay after exposure to a sub-MIC concentration of 1/2× MIC TBD. In conclusion, TBD exhibits antibacterial and anti-biofilm activity against S. aureus possibly by targeting the DnaK chaperone system.

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Data availability

The raw whole-genome sequencing data was posted in the Sequence Read Archive (SRA) database under BioProject accession number PRJNA673936 in NCBI.

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Author contributions

ZW and QD conceived and design this study. JG, YZ, and HC performed the experiment. DL and ZW interpret the reference and provided the information about the background. ZY analyzed the data. JG, ZW, and QD wrote the paper. All authors reviewed the manuscript.

Funding

This work was supported by the following grants: National Natural Science Foundation of China (No. 82172283); Natural Science Foundation of Guangdong Province, China (No.2020A1515011049, 2021A1515011727); Sanming Project of Medicine in Shenzhen (No.SMGC201705029); Shenzhen Key Medical Discipline ConstructionFund (No.SZXK06162); Science, Technology and Innovation Commission of Shenzhen Municipality of key funds (JCYJ20180508162403996) and basic research funds (JCYJ20180302144431923; JCYJ20180302144721183; JCYJ20180302144340004; JCYJ20180302144345028); the Shenzhen Nanshan District Scientific Research Program of the People’s Republic of China (No. NS009, NS066, NS144, NS140, NS117.

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Author notes

  1. These authors contributed equally: Jie Guo, Yufang Zhang, Hang Cheng

Authors and Affiliations

  1. Department of Infectious Diseases and Shenzhen Key Laboratory for Endogenous Infections, Huazhong University of Science and Technology Union Shenzhen Hospital, No. 89 Taoyuan Road, Nanshan District, Shenzhen, 518052, China

    Jie Guo, Yufang Zhang, Hang Cheng, Duoyun Li, Zhanwen Wang, Chengchun Chen, Zhijian Yu, Qiwen Deng & Zewen Wen

  2. Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, 518060, China

    Jie Guo, Zhijian Yu, Qiwen Deng & Zewen Wen

  3. Class of Biological Science, Shenzhen College of International Education, No. 3 Antuoshan 6th Rd, Futian District, Shenzhen, 518040, China

    Yufang Zhang

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  1. Jie Guo
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Corresponding authors

Correspondence to Qiwen Deng or Zewen Wen.

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The authors declare no competing interests.

Ethical approval

This study was approved by the Ethics Committee of Shenzhen Nanshan people’s Hospital, the 6th Affiliated Hospital of Shenzhen University Health Science Center. For this type of study, formal consent is not required.

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Supplementary information

Impact of TBD with different concentrations (1/4×, 1/2×, and 1× MIC) on the growth of S. aureus planktonic cells

41429_2022_515_MOESM2_ESM.jpg

Bacteria growth curve analysis of DnaK overexpression S. aureus isolate after treated with different concentrations of vancomycin

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Guo, J., Zhang, Y., Cheng, H. et al. Inhibition of Staphylococcus aureus and biofilm formation by the anthelminthic drug, triclabendazole. J Antibiot 75, 287–295 (2022). https://doi.org/10.1038/s41429-022-00515-9

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