Development of ebsulfur analogues as potent antibacterials against methicillin-resistant Staphylococcus aureus

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• 作者：Huy X. Ngo^&dagger ; ; Sanjib K. Shrestha^&dagger ; ; Keith D. Green^&dagger ; ; Sylvie Garneau-Tsodikova ; ^{sylviegtsodikova@uky.edu}
• 关键词：Antibiotic ; Benzisothiazolinone ; Biofilm ; ESKAPE ; Reactive oxygen species (ROS) ; Resistance
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 December 2016
• 年：2016
• 卷：24
• 期：24
• 页码：6298-6306
• 全文大小：1694 K
• 卷排序：24

文摘

Antibiotic resistance is a worldwide problem that needs to be addressed. Staphylococcus aureus is one of the dangerous “ESKAPE” pathogens that rapidly evolve and evade many current FDA-approved antibiotics. Thus, there is an urgent need for new anti-MRSA compounds. Ebselen (also known as 2-phenyl-1,2-benzisoselenazol-3(2H)-one) has shown promising activity in clinical trials for cerebral ischemia, bipolar disorder, and noise-induced hearing loss. Recently, there has been a renewed interest in exploring the antibacterial properties of ebselen. In this study, we synthesized an ebselen-inspired library of 33 compounds where the selenium atom has been replaced by sulfur (ebsulfur derivatives) and evaluated them against a panel of drug-sensitive and drug-resistant S. aureus and non-S. aureus strains. Within our library, we identified three outstanding analogues with potent activity against all S. aureus strains tested (MIC values mostly ⩽2 μg/mL), and numerous additional ones with overall very good to good antibacterial activity (1–7.8 μg/mL). We also characterized the time-kill analysis, anti-biofilm ability, hemolytic activity, mammalian cytotoxicity, membrane-disruption ability, and reactive oxygen species (ROS) production of some of these analogues.