Haloemodin as Novel Antibacterial Agent Inhibiting DNA Gyrase and Bacterial Topoisomerase I
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 acti...
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| Veröffentlicht in: | Journal of medicinal chemistry 2014-05, Vol.57 (9), p.3707-3714 |
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| creator | Duan, Feixia Li, Xiaohong Cai, Suping Xin, Guang Wang, Yanyan Du, Dan He, Shiliang Huang, Baozhan Guo, Xiurong Zhao, Hang Zhang, Rui Ma, Limei Liu, Yan Du, Qigen Wei, Zeliang Xing, Zhihua Liang, Yong Wu, Xiaohua Fan, Chengzhong Ji, Chengjie Zeng, Dequan Chen, Qianming He, Yang Liu, Xuyang Huang, Wen |
| description | 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. |
| doi_str_mv | 10.1021/jm401685f |
| format | Article |
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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.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm401685f</identifier><identifier>PMID: 24588790</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Anti-Bacterial Agents - pharmacology ; Anti-Bacterial Agents - therapeutic use ; Emodin - analogs & derivatives ; Emodin - pharmacology ; Enterococcus faecium - drug effects ; Enterococcus faecium - enzymology ; Keratitis - drug therapy ; Keratitis - microbiology ; Methicillin-Resistant Staphylococcus aureus - drug effects ; Methicillin-Resistant Staphylococcus aureus - enzymology ; Mice ; Microbial Sensitivity Tests ; Rabbits ; Topoisomerase I Inhibitors - pharmacology ; Topoisomerase I Inhibitors - therapeutic use ; Topoisomerase II Inhibitors - pharmacology ; Topoisomerase II Inhibitors - therapeutic use</subject><ispartof>Journal of medicinal chemistry, 2014-05, Vol.57 (9), p.3707-3714</ispartof><rights>Copyright © 2014 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-14dd4a8ea8cecd5dd65e6e719edb5549aac8c6218126bd6b58210fbbba8fb02c3</citedby><cites>FETCH-LOGICAL-a315t-14dd4a8ea8cecd5dd65e6e719edb5549aac8c6218126bd6b58210fbbba8fb02c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm401685f$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm401685f$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27055,27903,27904,56716,56766</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24588790$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Duan, Feixia</creatorcontrib><creatorcontrib>Li, Xiaohong</creatorcontrib><creatorcontrib>Cai, Suping</creatorcontrib><creatorcontrib>Xin, Guang</creatorcontrib><creatorcontrib>Wang, Yanyan</creatorcontrib><creatorcontrib>Du, Dan</creatorcontrib><creatorcontrib>He, Shiliang</creatorcontrib><creatorcontrib>Huang, Baozhan</creatorcontrib><creatorcontrib>Guo, Xiurong</creatorcontrib><creatorcontrib>Zhao, Hang</creatorcontrib><creatorcontrib>Zhang, Rui</creatorcontrib><creatorcontrib>Ma, Limei</creatorcontrib><creatorcontrib>Liu, Yan</creatorcontrib><creatorcontrib>Du, Qigen</creatorcontrib><creatorcontrib>Wei, Zeliang</creatorcontrib><creatorcontrib>Xing, Zhihua</creatorcontrib><creatorcontrib>Liang, Yong</creatorcontrib><creatorcontrib>Wu, Xiaohua</creatorcontrib><creatorcontrib>Fan, Chengzhong</creatorcontrib><creatorcontrib>Ji, Chengjie</creatorcontrib><creatorcontrib>Zeng, Dequan</creatorcontrib><creatorcontrib>Chen, Qianming</creatorcontrib><creatorcontrib>He, Yang</creatorcontrib><creatorcontrib>Liu, Xuyang</creatorcontrib><creatorcontrib>Huang, Wen</creatorcontrib><title>Haloemodin as Novel Antibacterial Agent Inhibiting DNA Gyrase and Bacterial Topoisomerase I</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>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.</description><subject>Animals</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Anti-Bacterial Agents - therapeutic use</subject><subject>Emodin - analogs & derivatives</subject><subject>Emodin - pharmacology</subject><subject>Enterococcus faecium - drug effects</subject><subject>Enterococcus faecium - enzymology</subject><subject>Keratitis - drug therapy</subject><subject>Keratitis - microbiology</subject><subject>Methicillin-Resistant Staphylococcus aureus - drug effects</subject><subject>Methicillin-Resistant Staphylococcus aureus - enzymology</subject><subject>Mice</subject><subject>Microbial Sensitivity Tests</subject><subject>Rabbits</subject><subject>Topoisomerase I Inhibitors - pharmacology</subject><subject>Topoisomerase I Inhibitors - therapeutic use</subject><subject>Topoisomerase II Inhibitors - pharmacology</subject><subject>Topoisomerase II Inhibitors - therapeutic use</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkD1PwzAQQC0EoqUw8AdQFiQYArZjp-5YCpRKVVnKxBD541JcJXaxE6T-ewItnZhOp3t60j2ELgm-I5iS-3XNMMkFL49Qn3CKUyYwO0Z9jClNaU6zHjqLcY0xzgjNTlGPMi7EcIT76P1FVh5qb6xLZEwW_guqZOwaq6RuIFjZbStwTTJzH1bZxrpV8rgYJ9NtkBES6UzycCCXfuNt9DX83mbn6KSUVYSL_Rygt-en5eQlnb9OZ5PxPJUZ4U1KmDFMCpBCgzbcmJxDDkMyAqM4ZyMptdA5JYLQXJlccUEJLpVSUpQKU50N0M3Ouwn-s4XYFLWNGqpKOvBtLLokGcN4yHiH3u5QHXyMAcpiE2wtw7YguPhpWRxaduzVXtuqGsyB_IvXAdc7QOpYrH0bXPflP6Jvk717Ow</recordid><startdate>20140508</startdate><enddate>20140508</enddate><creator>Duan, Feixia</creator><creator>Li, Xiaohong</creator><creator>Cai, Suping</creator><creator>Xin, Guang</creator><creator>Wang, Yanyan</creator><creator>Du, Dan</creator><creator>He, Shiliang</creator><creator>Huang, Baozhan</creator><creator>Guo, Xiurong</creator><creator>Zhao, Hang</creator><creator>Zhang, Rui</creator><creator>Ma, Limei</creator><creator>Liu, Yan</creator><creator>Du, Qigen</creator><creator>Wei, Zeliang</creator><creator>Xing, Zhihua</creator><creator>Liang, Yong</creator><creator>Wu, Xiaohua</creator><creator>Fan, Chengzhong</creator><creator>Ji, Chengjie</creator><creator>Zeng, Dequan</creator><creator>Chen, Qianming</creator><creator>He, Yang</creator><creator>Liu, Xuyang</creator><creator>Huang, Wen</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20140508</creationdate><title>Haloemodin as Novel Antibacterial Agent Inhibiting DNA Gyrase and Bacterial Topoisomerase I</title><author>Duan, Feixia ; 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Med. Chem</addtitle><date>2014-05-08</date><risdate>2014</risdate><volume>57</volume><issue>9</issue><spage>3707</spage><epage>3714</epage><pages>3707-3714</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>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.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>24588790</pmid><doi>10.1021/jm401685f</doi><tpages>8</tpages></addata></record> |
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| subjects | Animals Anti-Bacterial Agents - pharmacology Anti-Bacterial Agents - therapeutic use Emodin - analogs & derivatives Emodin - pharmacology Enterococcus faecium - drug effects Enterococcus faecium - enzymology Keratitis - drug therapy Keratitis - microbiology Methicillin-Resistant Staphylococcus aureus - drug effects Methicillin-Resistant Staphylococcus aureus - enzymology Mice Microbial Sensitivity Tests Rabbits Topoisomerase I Inhibitors - pharmacology Topoisomerase I Inhibitors - therapeutic use Topoisomerase II Inhibitors - pharmacology Topoisomerase II Inhibitors - therapeutic use |
| title | Haloemodin as Novel Antibacterial Agent Inhibiting DNA Gyrase and Bacterial Topoisomerase I |
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