Cationic amphiphilic scandenone derivatives as membrane-active anti-MRSA agents

Methicillin-resistant Staphylococcus aureus (MRSA) remains a major challenge in anti-infective therapy, highlighting the need for antibacterial agents with novel structures and mechanisms of action. Herein, a gram-scale preparation of the natural antibacterial isoflavone scandenone was established, enabling systematic structural optimization of this prenylated isoflavonoid scaffold. Guided by a cationic amphiphilic design strategy, a series of scandenone-derived quaternary ammonium derivatives were synthesized to enhance antibacterial activity and membrane targeting. Among them, compound 16c displayed the most favorable profile, with potent anti-MRSA activity, low hemolytic toxicity, rapid bactericidal activity, and a low propensity for resistance development. Mechanistic studies supported a primarily membrane-targeting mode of action, in which 16c preferentially associates with anionic phospholipid membranes and disrupts membrane integrity, with induction of intracellular ROS generation contributing to its bactericidal activity. The antibacterial efficacy of 16c was further validated in Galleria mellonella larvae and a murine MRSA infection model. These findings identify 16c as a promising membrane-active anti-MRSA lead and highlight cationic amphiphilic modification as a strategy for improving the antibacterial properties of prenylated isoflavonoid scaffolds.