Thiazolidione derivatives targeting the histidine kinase YycG are effective against both planktonic and biofilm-associated Staphylococcus epidermidis

• Published in: Acta pharmacologica Sinica Vol. 33; no. 3; pp. 418 - 425
• Main Authors: Huang, Ren-zheng, Zheng, Li-kang, Liu, Hua-yong, Pan, Bin, Hu, Jian, Zhu, Tao, Wang, Wei, Jiang, Dan-bin, Wu, Yang, Wu, You-cong, Han, Shi-qing, Qu, Di
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2012; Nature Publishing Group
• Subjects: Anti-Bacterial Agents - pharmacology; Biofilms - drug effects; Biomedical and Life Sciences; Biomedicine; Histidine Kinase; Immunology; Internal Medicine; Medical Microbiology; MIC值; Original; original-article; Pharmacology/Toxicology; Plankton - drug effects; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Staphylococcal Infections - drug therapy; Staphylococcal Infections - metabolism; Staphylococcus epidermidis; Staphylococcus epidermidis - drug effects; Staphylococcus epidermidis - metabolism; Thiazoles - pharmacology; Vaccine; 共聚焦激光扫描显微镜; 最低杀菌浓度; 激酶; 生物膜; 组氨酸; 衍生物; 表皮葡萄球菌; antibacterial agent; minimal inhibitory concentration; biofilm-killing activity; half maximal inhibitory concentration
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2011.166

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 pL 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 pp=,/mL, respectively. The MBC values of these derivatives were 48.6, 52.2, 12.4, 52.6, 12.4, and 6.2 pg/mL, respectively. The derivatives killed all bacteria in immature （6 h-old） biofilms and eliminated the biofllm 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 erythro- cytes. Conclusion： The bactericidal and biofilm-killing activities of the new anti-YycG compounds were significantly better than the parent Compound 2.