Novel membrane-targeting isoxanthohumol-amine conjugates for combating methicillin-resistant Staphylococcus aureus
Ruige Yang1, Wanqing Cheng2, Meijuan Huang2
1Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan Province, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450001, Henan Province, China.
Abstract:
Methicillin-resistant Staphylococcus aureus (MRSA) is a widespread pathogen causing clinical infections and is multi-resistant to many antibiotics, making it urgent need to develop novel antibacterials to combat MRSA. Here, a series of novel isoxanthohumol-amine conjugates were synthesized as antibacterials. After bioactivity evaluation, a compound E2 was obtained, which showed excellent antibacterial activity against S. aureus and clinical MRSA isolates (MICs = 0.25-1 μg/mL), superior to vancomycin, and with negligible hemolysis and good membrane selectivity. Additionally, E2 exhibited fast bacterial killing, less susceptible to resistance, relatively low cytotoxicity, and good plasma stability. Mechanism investigation revealed that E2 can disrupt bacterial membranes by specifically binding to phosphatidylglycerol on the bacterial membrane, thus causing elevated intracellular ROS and leakage of DNA and proteins, and ultimately killing bacteria. Noticeably, E2 displayed a good in vivo safety profile and better in vivo therapeutic efficacy than the same dose of vancomycin, allowing it to be a potential antibacterial to conquer MRSA infections.
