Antibacterial and antibiofilm activities of thiazolidine-2,4-dione and 4-thioxo-thiazolidin-2-one derivatives against multidrug-resistant Staphylococcus aureus clinical isolates.

Aims: Antimicrobial resistance is one of the highest priorities in global public health with Staphylococcus aureus among the most important microorganisms due to its rapidly evolving antimicrobial resistance. Despite all the efforts of antimicrobial stewardship, research and development of new antimicrobials are still imperative. The thiazolidine ring is considered a privileged structure for the development of new antimicrobials. This study aimed to compare the antibacterial effects of two analogue series of thiazolidine-2,4-dione and 4-thioxo-thiazolidin-2-one against multidrug-resistant Staph. aureus clinical isolates.

Methods And Results: The derivatives 1a, 2a and 2b exhibited MIC between 1-32 μg ml , with time-to-kill curves showing a bactericidal effect up to 24 h. In the antibiofilm assay, the most active derivatives were able to inhibit about 90% of biofilm formation. The 4-thioxo-thiazolidine-2-one derivatives were more active against planktonic cells, while the thiazolidine-2,4-dione derivatives were able to disrupt about 50% of the preformed biofilm. In the in vivo infection model using Caenorhabditis elegans as a host, the derivatives 1a, 2a and 2b increased nematode survival with a concentration-dependent effect. Exposure of Staph. aureus to the derivatives 2a and 2b induced surface changes and decrease cell size. None of the derivatives was cytotoxic for human peripheral blood mononuclear cells (PBMC) but showed moderate cytotoxicity for L929 fibroblasts.

Conclusion: The 5-(3,4-dichlorobenzylidene)-4-thioxothiazolidin-2-one (2b) was the most active derivative against Staph. aureus and showed higher selective indices.

Significance And Impact Of The Study: 4-thioxo-thiazolidin-2-one is a promising scaffold for the research and development of new antimicrobial drugs against multidrug-resistant Staph. aureus.