Improving Activity of New Arylurea Agents against Multidrug-Resistant and Biofilm-Producing Staphylococcus epidermidis

Multidrug-resistant (MDR) strains of Staphylococcus epidermidis (S. epidermidis), prevalent in hospital environments, contribute to increased morbidity and mortality, especially among newborns, posing a critical concern for neonatal sepsis. In response to the pressing demand for novel Antibacterial therapies, we present findings from synthetic chemistry and structure-activity relationship studies focused on arylsulfonamide/arylurea derivatives of aryloxy[1-(thien-2-yl)propyl]piperidines. Through bioisosteric replacement of the sulfonamide fragment with a urea moiety, compound 25 was identified, demonstrating potent bacteriostatic activity against clinical multidrug-resistant S. epidermidis strains (MIC₅₀ and MIC₉₀ = 1.6 and 3.125 μg/mL). Importantly, it showed activity against linezolid-resistant strains and exhibited selectivity over mammalian cells. Compound 25 displayed antibiofilm-forming properties against clinical S. epidermidis strains and demonstrated the capacity to eliminate existing biofilm layers. Additionally, it induced complete depolarization of the Bacterial membrane in clinical S. epidermidis strains. In light of these findings, targeting Bacterial cell membranes with compound 25 emerges as a promising strategy in the fight against multidrug-resistant S. epidermidis strains.