Inhibition of Growth and Biofilm Formation in <i>Staphylococcus aureus</i> by LLY-507

The emergence of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) as a prevalent antibiotic-resistant pathogen underscores the urgent need for novel antibacterial agents. This study investigates the potential of LLY-507 against Gram-positive bacteria, particularly <i>S. aureus</i>, focusing on its antibacterial and antibiofilm properties. Here, our data exhibited the favorable antibacterial activity of LLY-507 with MIC₅₀ and MIC₉₀ values of 25 μM against <i>S. aureus</i>. Additionally, LLY-507 at sub-MIC concentrations effectively reduced the planktonic growth and biofilm formation of <i>S. aureus</i>. Proteomic analysis of <i>S. aureus</i> treated with LLY-507 revealed the classification of the functional proteins with significant expression level alterations in bacterial metabolism, particularly amino acid biosynthesis. Furthermore, we demonstrated the disruption of <i>S. aureus</i> cell integrity by LLY-507 through scanning electron microscopy (SEM) assay, membrane permeability assays, and direct binding experiments between LLY-507 and cardiolipin. Lastly, the effectiveness of LLY-507 was proven in vivo using the <i>Galleria mellonella</i> infection model. Overall, these findings highlight the promising antibacterial and antibiofilm activities of LLY-507 against <i>S. aureus</i> and provide insights into its mechanism of action, implicating its potential as a lead compound for developing novel antibacterial agents targeting Gram-positive bacteria.