New Tetraphenylethylene Benzoic Acid Derivatives as Antibacterial Agents for Gram-Positive Bacteria with Ultralow Inhibition Concentration

The misuse of antibiotics has intensified the emergence of drug-resistant bacteria. The diversity of chemical structures offers a crucial foundation for developing novel small-molecule antibacterials. New chemical scaffolds may hold significant potential for combating drug-resistant bacteria. In this study, a series of benzoic acid derivatives featuring a tetraphenylethylene (TPE) core were designed to modulate their pK_a by incorporating various electron-donating and electron-withdrawing groups. This approach led to the development of a series of effective Staphylococcus aureus therapeutic agents. Among these compounds, the nitro-substituted tetraphenylethylene benzoic acid derivative (NOA) exhibits an ultralow minimum inhibitory concentration (MIC = 0.04 μg/mL) against S. aureus, while MIC of the traditional antibiotic vancomycin was 0.13 μg/mL. NOA achieved a 99% elimination rate of S. aureus at a 0.16 μg/mL and displayed antibacterial activity against S. aureus biofilm at 0.32 μg/mL. NOA could effectively treat wound infections caused by S. aureus in infected mouse models. This study provides valuable advice about the chemical substituents for designing new antibacterial agents.