Abstract
Aim:
To evaluate the efficacies of six derivatives of Compound 2, a novel YycG histidine kinase inhibitor with the thiazolidione core structure in the treatment of medical device-related biofilm infections.
Methods:
The minimal inhibitory concentration (MIC) of the derivatives was determined using the macrodilution broth method, and the minimal bactericidal concentration (MBC) was obtained via sub-culturing 100 μL from each negative tube from the MIC assay onto drug-free Mueller-Hinton agar plates. Biofilm-killing effect for immature (6 h-old) biofilms was examined using a semiquantitative plate assay, and the effect on mature (24 h-old) biofilms was observed under a confocal laser scanning microscope (CLSM).
Results:
The derivatives potently suppressed the growth of Staphylococcus epidermidis. The MIC values of the derivatives H2-10, H2-12, H2-20, H2-29, H2-27, and H2-28 on S epidermidis ATCC 35984 were 24.3, 6.5, 6.2, 3.3, 3.1, and 1.5 μg/mL, respectively. The MBC values of these derivatives were 48.6, 52.2, 12.4, 52.6, 12.4, and 6.2 μg/mL, respectively. The derivatives killed all bacteria in immature (6 h-old) biofilms and eliminated the biofilm proliferation. The derivatives also displayed strong bactericidal activities toward cells in mature (24 h-old) biofilms, whereas they showed low cytotoxicity and hemolytic activity toward Vero cells and human erythrocytes.
Conclusion:
The bactericidal and biofilm-killing activities of the new anti-YycG compounds were significantly better than the parent Compound 2.
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Acknowledgements
We would like to thank Prof Guo-qiang LIN, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, for his invaluable advice. This work was supported by the Program of Ministry of Science and Technology of China (2012ZX09301002-005, 2012ZX10003008-010, and 2010DFA32100), the National Natural Science Foundation of China (30800036, 20942006, 21072095, and 81101214), the Scientific Technology Development Foundation of Shanghai (08JC1401600 and 10410700600), the High-Tech Research and Development Program of China (2006AA02A253), and the Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP) (20100071120049).
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Huang, Rz., Zheng, Lk., Liu, Hy. et al. Thiazolidione derivatives targeting the histidine kinase YycG are effective against both planktonic and biofilm-associated Staphylococcus epidermidis. Acta Pharmacol Sin 33, 418–425 (2012). https://doi.org/10.1038/aps.2011.166
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DOI: https://doi.org/10.1038/aps.2011.166
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