<b>A novel quorum sensing inhibitor targets the LuxS/AI-2 pathway to suppress virulence and potentiate antibiotics in multidrug-resistant </b><b><i>Klebsiella pneumoniae</i></b>

Importantly, MMSB at 32 µg/mL significantly enhanced the antibacterial activity of kanamycin, streptomycin, azithromycin, and chloramphenicol, increasing inhibition rates by 38%, 29%, 26%, and 20%, respectively. In a <i>Galleria mellonella</i> infection model, combining MMSB with kanamycin elevates larval survival to 70% at 12 h and 60% at 72 h, versus 20% for monotherapies. RT qPCR showed downregulation of key genes within QS cascade, including luxS, lsrK, mrkA, and wbbM.

Surface plasmon resonance confirmed direct binding to LuxS with KD of 3.714×10⁻⁵ M, and molecular docking revealed stable accommodation in the active pocket, stabilized by zinc and key residues. Transcriptomic profiling reveals that MMSB disrupted amino acid biosynthesis, ABC transporters, and cell envelope biogenesis pathways. Collectively, MMSB acts as a promising anti virulence adjuvant by targeting the LuxS/AI 2 cascade and remodeling metabolic networks to restore antibiotic susceptibility.</p>