<i>De Novo</i> 3-(Phenylcarbamoyl) Benzoate Analogues: Efficacy against Multidrug-Resistant <i>S. aureus</i> 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 (<b>L1-L17</b>) as potent antimicrobial agents targeting <i>Staphylococcus aureus</i> infections. The lead compounds <b>L8</b>, <b>L13</b>, <b>L14</b>, and <b>L15</b> demonstrated significant activity against methicillin- and vancomycin-resistant <i>S. aureus</i> (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 <i>in vitro</i>, <i>in silico</i>, and <i>in vivo</i> analyses identified <b>L13</b> and <b>L15</b> 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 <i>S. aureus</i>, particularly for hospital-acquired infections, offering a promising avenue in the fight against antimicrobial resistance.