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


CONCLUSIONS
The bactericidal and biofilm-killing activities of the new anti-YycG compounds were significantly better than the parent Compound 2.
Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Institute of Medical Microbiology, Shanghai Medical College of Fudan University, China.
Ren-zheng
RZ
Huang
Li-kang
LK
Zheng
Hua-yong
HY
Liu
Bin
B
Pan
Jian
J
Hu
Tao
T
Zhu
Wei
W
Wang
Dan-bin
DB
Jiang
Yang
Y
Wu
You-cong
YC
Wu
Shi-qing
SQ
Han
Di
D
Qu
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D000071677:Histidine Kinase; D010933:Plankton / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000378:metabolism; D013212:Staphylococcus epidermidis / Q000187:drug effects* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D047428:Protein Kinase Inhibitors; D013844:Thiazoles; D011494:Protein Kinases; D000071677:Histidine Kinase; C515949:YycG protein, Staphylococcus epidermidis