Mechanism of antibacterial and antibiofilm of thiazolidinone derivative TD-H2-A against Staphylococcus aureus

Staphylococcus aureus is one of the most common pathogens causing widespread infections. It has been demonstrated that thiazolidinone derivative (TD-H2-A), a small molecule compound that targets WalK protein through high-throughput screening, exerts antibacterial and anti-biofilm effects on S. aureus. In this study, we further ascertained the impact of TD-H2-A on biofilms at different stages. The phosphorylation assay and RNA sequencing were carried out to elucidate the underlying mechanism. The results revealed that TD-H2-A inhibited WalK autophosphorylation, implying that the antibacterial effect of TD-H2-A may be achieved by inhibiting the activity of WalK. The transcriptome analysis showed that TD-H2-A treatment induced 994 differentially expressed genes (DEGs), of which, 481 were upregulated and 513 were downregulated. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that 43 among 58 genes involved in ribosome synthesis were upregulated, and the transcript levels of the genes responsible for membrane transport were altered significantly. According to our research, TD-H2-A has an antibacterial mechanism with multitarget and multipathway. This study provided new ideas for the development of new drug target screening against S. aureus infections.