De Novo 3‑(Phenylcarbamoyl) Benzoate Analogues: Efficacy against Multidrug-Resistant S. aureus and Elucidation of the Biodistribution Profile

This study presents the first design, synthesis, and characterization of a novel library of carboxylate analogues of 3-(phenylcarbamoyl) benzoate (L1–L17) as potent antimicrobial agents targeting Staphylococcus aureus infections. The lead compounds L8, L13, L14, and L15 demonstrated significant activity against methicillin- and vancomycin-resistant S. aureus (MRSA and VRSA, respectively) with MIC values of 2–8 μg/mL. Mechanistic investigations using scanning electron microscopy (SEM) and atomic force microscopy (AFM) revealed bacterial membrane disruption as the primary mode of action. Further in vitro, in silico, and in vivo analyses identified L13 and L15 as the most promising candidates. A translational study using a BALB/c mouse skin abscess model confirmed their therapeutic potential, supported by biodistribution profiling via LC/Q-TOF mass spectrometry. These findings mark a significant step toward developing novel antibiotics against S. aureus, particularly for hospital-acquired infections, offering a promising avenue in the fight against antimicrobial resistance.