Development of Membrane-Targeting Osthole Derivatives Containing Pyridinium Quaternary Ammonium Moieties with Potent Anti-Methicillin-Resistant <i>Staphylococcus aureus</i> Properties

Abstract

Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) is a leading cause of hospital- and community-acquired infections, necessitating the development of novel antibacterials. Here, we designed and synthesized 30 osthole derivatives with pyridinium quaternary ammonium moieties. <i>In vitro</i> bioassay showed that compounds <b>8u</b> and <b>8ac</b> exhibited potent antibacterial activity against <i>S. aureus</i> ATCC 29213 and ten clinical MRSA isolates (MIC = 0.5-1 μg/mL), with low hemolytic activity, rapid bactericidal effects, and minimal resistance induction. In MRSA-infected mouse models of skin abscesses and sepsis, <b>8u</b> and <b>8ac</b> also displayed excellent antibacterial effects and safety, which were comparable to vancomycin. Mechanistic studies revealed that <b>8u</b> and <b>8ac</b> selectively target bacterial membranes via binding to phosphatidylglycerol (PG), increasing intracellular reactive oxygen species (ROS), inducing content leakage, and ultimately causing bacterial death. These findings suggest <b>8u</b> and <b>8ac</b> as promising novel lead candidates for anti-MRSA drug development.