A low cytotoxicity antibacterial agent with benzothiazole scaffold for MRSA infection treatment.

Antimicrobial resistance (AMR) is a serious threat to the human healthcare system due to the loss in efficacy of existing antibiotics, increasing mortality and morbidity, and higher treatment costs. Benzothiazole is a common scaffold in drug design, but no antimicrobial agents based on this scaffold structure are used clinically. In this study, a series of benzothiazole analogues were designed and synthesized as novel antibacterial agents. Among these analogues, compound 7k exhibited potent antibacterial activity against S. aureus (ATCC 29213), MRSA (ATCC BAA41), and MRSA (ATCC 43300) with a MIC value of 4 μg/mL. Under this concentration, compound 7k inhibited more than 80% of S. aureus biofilm formation. Notably, compound 7k showed low cell cytotoxicity (CC50 > 200 μM), hemolytic activity (HC50 > 200 μM), and high selectivity to the bacterial cell membrane. Mechanistic studies revealed that the bacterial cell membrane is the primary drug target of compound 7k. Moreover, compound 7k exhibited negligible skin toxicity and low acute oral toxicity. In vivo animal tests verified that compound 7k promoted the healing of infected skin wounds in mice. Taken together, compound 7k has therapeutic potential for clinical infections caused by MRSA strains.