Haloemodin as Novel Antibacterial Agent Inhibiting DNA Gyrase and Bacterial Topoisomerase I

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• 作者：Feixia Duan ; Xiaohong Li ; Suping Cai ; Guang Xin ; Yanyan Wang ; Dan Du ; Shiliang He ; Baozhan Huang ; Xiurong Guo ; Hang Zhao ; Rui Zhang ; Limei Ma ; Yan Liu ; Qigen Du ; Zeliang Wei ; Zhihua Xing ; Yong Liang ; Xiaohua Wu ; Chengzhong Fan ; Chengjie Ji ; Dequan Zeng ; Qianming Chen ; Yang He ; Xuyang Liu ; Wen Huang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：May 8, 2014
• 年：2014
• 卷：57
• 期：9
• 页码：3707-3714
• 全文大小：419K
• 年卷期：v.57,no.9(May 8, 2014)
• ISSN：1520-4804

文摘

Drug-resistant bacterial infections and lack of available antibacterial agents in clinical practice are becoming serious risks to public health. We synthesized a new class of haloemodins by modifying a traditional Chinese medicine component, emodin. The novel haloemodin exerts strong inhibitory activity on bacterial topoisomerase I and DNA gyrase, and not on the topoisomerases of human origin. In principle, it shows remarkable antibacterial activities against laboratory and clinically isolated Gram-positive bacteria, including vancomycin-resistant Enterococcus faecium and methicillin-resistant Staphylococcus aureus. We further expanded its antibacterial spectrum into against Gram-negative bacteria with the assistance of polymyxin B nonapeptide, which helps haloemodin to penetrate through the bacterial outer membrane. Finally, the therapeutic effect of haloemodin in vivo was confirmed in curing S. aureus-induced keratitis on rabbit model. With distinctive structural difference from the antibiotics we used, the haloemodins are of value as promising antibacterial pharmacophore, especially for combat the infections caused by drug-resistant pathogens.