Dithioether Inhibitors of Bacterial RNA Polymerase–Sigma Factor Interactions Exhibit In Vivo Efficacy against MRSA

Antimicrobial resistance (AMR) represents a critical and escalating global health threat, necessitating the development of novel antibacterial agents. Herein, we describe a new series of dithioether-based bacterial transcription inhibitors that target RNA polymerase (RNAP) and its transcription initiation factor σ. These compounds, designed through rational modification of established scaffolds, demonstrate potent in vitro antimicrobial activity against Gram-positive pathogens, including drug-resistant Staphylococcus aureus, with minimum inhibitory concentrations as low as 0.5 μg/mL. Mechanistic studies reveal that these inhibitors bind to the clamp-helix region of the RNAP β' subunit, thereby disrupting σ factor binding and effectively inhibiting bacterial transcription. Pharmacokinetic profiling indicates preferential accumulation in the bloodstream, which correlates with significant therapeutic efficacy in a murine sepsis model. Collectively, these findings establish dithioether scaffolds as a promising platform for the development of new antibacterial agents to address the urgent need for effective therapies against resistant bacterial infections.