The escalating crisis of antibiotics against Gram negative bacteria resistance demands innovative strategies to combat recalcitrant intracellular pathogens. We reposition RS 17053, an α1A-adrenoceptor antagonist with unexplored antibacterial function, as a mechanistically distinct broad-spectrum antibiotic. We proved RS 17053 has strong binding ability with Class A penicillin binding proteins (PBPs), which overcomes the β-lactam barrier by penetrating host cells and disrupts the biosynthesis of peptidoglycan by uniquely targeting MrcA/MecA. RS 17053 eradicated Gram-negative (Brucella, Salmonella) and Gram-positive (Methicillin resistant Staphylococcus aureus, MRSA) pathogens in vitro (MICs 0.25-4 μg/mL) and eliminated intracellular Brucella within macrophages at 8 μg/mL. Crucially, upon serial passaging under drug pressure, RS 17053 showed a slower progression to high-level resistance. In murine zoonotic infection models, 10 mg/kg/day RS 17053 achieved higher survival rate by caused a 2-log CFU/mL reduction in organs and normalizing pro-inflammatory cytokines. Multi-omics and phenotypic analyses confirmed selective PBP targeting, causing peptidoglycan collapse and bacterial lysis. This work has provided a promising therapeutic against intractable intracellular infections.
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