Benzenesulfonyl thiazoloimines as unique multitargeting antibacterial agents towards Enterococcus faecalis

New efficient antimicrobial agents are urgently needed to combat invasive multidrug-resistant pathogens in-fections. Structurally unique benzenesulfonyl thiazoloimines (BSTIs) were exploited as novel potential anti-bacterial victors to confront terrific drug resistance. Some developed BSTIs exerted effectively antimicrobial efficacy against the tested strains. Notably, 2-pyridyl BSTI 14d exhibited good antibacterial activity against E. faecalis with MIC value of 1 mu g/mL, which was superior to sulfathiazole and norfloxacin. The most active compound 14d not only showed rapid bactericidal properties and impeded E. faecalis biofilm formation to effectually relieve the development of drug resistance, but also performed low toxicity toward human red blood cells, human normal squamous epithelial cells and human non-neoplastic colon epithelial cells. Mechanistic investigation demonstrated that molecule 14d could exert efficient membrane destruction leading to the leakage of intracellular materials and metabolism inhibition, cause oxidative damage of E. faecalis through accumulation of excess reactive oxygen species and reduction of glutathione activity, and intercalate into DNA to hinder replication of DNA. Molecular docking indicated that the formation of 14d-dihydrofolate synthetase supramo-lecular complex could hinder the function of this enzyme. ADME analysis displayed that compound 14d possessed promising pharmacokinetic properties. These findings suggested that the newly developed benzene-sulfonyl thiazoloimines with multitargeting antibacterial potential provided a new possibility for evading resistance.

Automated summary

Newly developed benzene-sulfonyl thiazoloimines (BSTIs) with unique structure have shown promising antibacterial potential against drug-resistant pathogens, with 2-pyridyl BSTI 14d being particularly effective against E. faecalis. Compound 14d exhibited rapid bactericidal properties, inhibited biofilm formation, and displayed low toxicity towards human cells. Mechanistic investigations revealed that compound 14d disrupted cell membranes, caused oxidative damage, and hindered DNA replication. These findings suggest that BSTIs could provide a new possibility for overcoming drug resistance.