Lauric Acid- and BDSF-Derived N-Acyl Sulfonamides as Potent Antibiofilm and Antivirulence Agents against Staphylococcus aureus.

Biofilm-associated Staphylococcus aureus infections remain difficult to treat using conventional antibiotics. Herein, we report the synthesis and biological evaluation of lauric acid- and BDSF-derived N-acyl sulfonamides as antibiofilm and antivirulence agents. Structure-activity relationship (SAR) analysis identified 4-tert-butylphenyl sulfonyldodecenamide (59) as a lead compound with a minimum inhibitory concentration of 5 μg/mL and >60% inhibition of MSSA and MRSA biofilm formation at sub-minimum inhibitory concentration levels. Microscopy confirmed marked reductions in biofilm biomass and thickness. The lead compound synergized with gentamicin and tobramycin, suppressed hemolysis, slime production, metabolic activity, and cell-surface hydrophobicity, and induced intracellular reactive oxygen species. qRT-PCR revealed downregulation of key virulence regulators (agrA, RNAIII, saeR, and seb), indicating disruption of quorum-sensing circuitry. SAR modeling rationalized steric and electronic requirements for activity. Low toxicity in plant, nematode, and mammalian models highlights bioisosteric N-acyl sulfonamides as promising antivirulence scaffolds for combating S. aureus biofilm infections.