Amino Acid Modified Xanthone Derivatives: Novel, Highly Promising Membrane-Active Antimicrobials for Multidrug-Resistant Gram-Positive Bacterial Infections
Antibiotic resistance is a critical global health care crisis requiring urgent action to develop more effective antibiotics. Utilizing the hydrophobic scaffold of xanthone, we identified three components that mimicked the action of an antimicrobial cationic peptide to produce membrane-targeting anti...
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| Veröffentlicht in: | Journal of medicinal chemistry 2015-01, Vol.58 (2), p.739-752 |
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| creator | Koh, Jun-Jie Lin, Shuimu Aung, Thet Tun Lim, Fanghui Zou, Hanxun Bai, Yang Li, Jianguo Lin, Huifen Pang, Li Mei Koh, Wee Luan Salleh, Shuhaida Mohamed Lakshminarayanan, Rajamani Zhou, Lei Qiu, Shengxiang Pervushin, Konstantin Verma, Chandra Tan, Donald T. H Cao, Derong Liu, Shouping Beuerman, Roger W |
| description | Antibiotic resistance is a critical global health care crisis requiring urgent action to develop more effective antibiotics. Utilizing the hydrophobic scaffold of xanthone, we identified three components that mimicked the action of an antimicrobial cationic peptide to produce membrane-targeting antimicrobials. Compounds 5c and 6, which contain a hydrophobic xanthone core, lipophilic chains, and cationic amino acids, displayed very promising antimicrobial activity against multidrug-resistant Gram-positive bacteria, including MRSA and VRE, rapid time–kill, avoidance of antibiotic resistance, and low toxicity. The bacterial membrane selectivity of these molecules was comparable to that of several membrane-targeting antibiotics in clinical trials. 5c and 6 were effective in a mouse model of corneal infection by S. aureus and MRSA. Evidence is presented indicating that 5c and 6 target the negatively charged bacterial membrane via a combination of electrostatic and hydrophobic interactions. These results suggest that 5c and 6 have significant promise for combating life-threatening infections. |
| doi_str_mv | 10.1021/jm501285x |
| format | Article |
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H ; Cao, Derong ; Liu, Shouping ; Beuerman, Roger W</creator><creatorcontrib>Koh, Jun-Jie ; Lin, Shuimu ; Aung, Thet Tun ; Lim, Fanghui ; Zou, Hanxun ; Bai, Yang ; Li, Jianguo ; Lin, Huifen ; Pang, Li Mei ; Koh, Wee Luan ; Salleh, Shuhaida Mohamed ; Lakshminarayanan, Rajamani ; Zhou, Lei ; Qiu, Shengxiang ; Pervushin, Konstantin ; Verma, Chandra ; Tan, Donald T. H ; Cao, Derong ; Liu, Shouping ; Beuerman, Roger W</creatorcontrib><description>Antibiotic resistance is a critical global health care crisis requiring urgent action to develop more effective antibiotics. Utilizing the hydrophobic scaffold of xanthone, we identified three components that mimicked the action of an antimicrobial cationic peptide to produce membrane-targeting antimicrobials. Compounds 5c and 6, which contain a hydrophobic xanthone core, lipophilic chains, and cationic amino acids, displayed very promising antimicrobial activity against multidrug-resistant Gram-positive bacteria, including MRSA and VRE, rapid time–kill, avoidance of antibiotic resistance, and low toxicity. The bacterial membrane selectivity of these molecules was comparable to that of several membrane-targeting antibiotics in clinical trials. 5c and 6 were effective in a mouse model of corneal infection by S. aureus and MRSA. Evidence is presented indicating that 5c and 6 target the negatively charged bacterial membrane via a combination of electrostatic and hydrophobic interactions. These results suggest that 5c and 6 have significant promise for combating life-threatening infections.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm501285x</identifier><identifier>PMID: 25474410</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Amino Acids - pharmacology ; Animals ; Anti-Bacterial Agents - chemical synthesis ; Anti-Bacterial Agents - pharmacology ; Cell Membrane - drug effects ; Drug Resistance, Multiple, Bacterial ; Gram-Positive Bacterial Infections - drug therapy ; Magnetic Resonance Spectroscopy ; Mice ; Microbial Sensitivity Tests ; Rabbits ; Structure-Activity Relationship ; Unilamellar Liposomes ; Xanthones - chemical synthesis ; Xanthones - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2015-01, Vol.58 (2), p.739-752</ispartof><rights>Copyright © 2014 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a381t-ae3c76884ee270928a7599eff5393c7fcf21e211d91b8d6ab83413875a565ca53</citedby><cites>FETCH-LOGICAL-a381t-ae3c76884ee270928a7599eff5393c7fcf21e211d91b8d6ab83413875a565ca53</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/jm501285x$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm501285x$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25474410$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Koh, Jun-Jie</creatorcontrib><creatorcontrib>Lin, Shuimu</creatorcontrib><creatorcontrib>Aung, Thet Tun</creatorcontrib><creatorcontrib>Lim, Fanghui</creatorcontrib><creatorcontrib>Zou, Hanxun</creatorcontrib><creatorcontrib>Bai, Yang</creatorcontrib><creatorcontrib>Li, Jianguo</creatorcontrib><creatorcontrib>Lin, Huifen</creatorcontrib><creatorcontrib>Pang, Li Mei</creatorcontrib><creatorcontrib>Koh, Wee Luan</creatorcontrib><creatorcontrib>Salleh, Shuhaida Mohamed</creatorcontrib><creatorcontrib>Lakshminarayanan, Rajamani</creatorcontrib><creatorcontrib>Zhou, Lei</creatorcontrib><creatorcontrib>Qiu, Shengxiang</creatorcontrib><creatorcontrib>Pervushin, Konstantin</creatorcontrib><creatorcontrib>Verma, Chandra</creatorcontrib><creatorcontrib>Tan, Donald T. H</creatorcontrib><creatorcontrib>Cao, Derong</creatorcontrib><creatorcontrib>Liu, Shouping</creatorcontrib><creatorcontrib>Beuerman, Roger W</creatorcontrib><title>Amino Acid Modified Xanthone Derivatives: Novel, Highly Promising Membrane-Active Antimicrobials for Multidrug-Resistant Gram-Positive Bacterial Infections</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Antibiotic resistance is a critical global health care crisis requiring urgent action to develop more effective antibiotics. Utilizing the hydrophobic scaffold of xanthone, we identified three components that mimicked the action of an antimicrobial cationic peptide to produce membrane-targeting antimicrobials. Compounds 5c and 6, which contain a hydrophobic xanthone core, lipophilic chains, and cationic amino acids, displayed very promising antimicrobial activity against multidrug-resistant Gram-positive bacteria, including MRSA and VRE, rapid time–kill, avoidance of antibiotic resistance, and low toxicity. The bacterial membrane selectivity of these molecules was comparable to that of several membrane-targeting antibiotics in clinical trials. 5c and 6 were effective in a mouse model of corneal infection by S. aureus and MRSA. Evidence is presented indicating that 5c and 6 target the negatively charged bacterial membrane via a combination of electrostatic and hydrophobic interactions. These results suggest that 5c and 6 have significant promise for combating life-threatening infections.</description><subject>Amino Acids - pharmacology</subject><subject>Animals</subject><subject>Anti-Bacterial Agents - chemical synthesis</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Cell Membrane - drug effects</subject><subject>Drug Resistance, Multiple, Bacterial</subject><subject>Gram-Positive Bacterial Infections - drug therapy</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Mice</subject><subject>Microbial Sensitivity Tests</subject><subject>Rabbits</subject><subject>Structure-Activity Relationship</subject><subject>Unilamellar Liposomes</subject><subject>Xanthones - chemical synthesis</subject><subject>Xanthones - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkMtOwzAQRS0EglJY8APIGxZIBPyIG4ddeCNRQAgkdpGTjIurxK7stIJv4WdxKbBiNYs5c-bqIrRHyTEljJ5MO0Eok-J9DQ2oYCRJJUnX0YAQxhI2YnwLbYcwJYRwyvgm2mIizdKUkgH6LDpjHS5q0-Cxa4w20OBXZfs3ZwFfgDcL1ZsFhFN87xbQHuEbM3lrP_Cjd50Jxk7wGLrKKwtJUS9JXNjedKb2rjKqDVg7j8fztjeNn0-SJwgm9NGPr73qkkcXzPfRmar7-Ey1-NZqiCJnww7a0NEAuz9ziF6uLp_Pb5K7h-vb8-IuUVzSPlHA62wkZQrAMpIzqTKR56C14Hnc6FozCozSJqeVbEaqkjylXGZCiZGoleBDdLjyxswheNDlzJtO-Y-SknJZcPlXcGT3V-xsXnXQ_JG_jUbgYAWoOpRTN_c2Rv9H9AWx5YTN</recordid><startdate>20150122</startdate><enddate>20150122</enddate><creator>Koh, Jun-Jie</creator><creator>Lin, Shuimu</creator><creator>Aung, Thet Tun</creator><creator>Lim, Fanghui</creator><creator>Zou, Hanxun</creator><creator>Bai, Yang</creator><creator>Li, Jianguo</creator><creator>Lin, Huifen</creator><creator>Pang, Li Mei</creator><creator>Koh, Wee Luan</creator><creator>Salleh, Shuhaida Mohamed</creator><creator>Lakshminarayanan, Rajamani</creator><creator>Zhou, Lei</creator><creator>Qiu, Shengxiang</creator><creator>Pervushin, Konstantin</creator><creator>Verma, Chandra</creator><creator>Tan, Donald T. H</creator><creator>Cao, Derong</creator><creator>Liu, Shouping</creator><creator>Beuerman, Roger W</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></search><sort><creationdate>20150122</creationdate><title>Amino Acid Modified Xanthone Derivatives: Novel, Highly Promising Membrane-Active Antimicrobials for Multidrug-Resistant Gram-Positive Bacterial Infections</title><author>Koh, Jun-Jie ; Lin, Shuimu ; Aung, Thet Tun ; Lim, Fanghui ; Zou, Hanxun ; Bai, Yang ; Li, Jianguo ; Lin, Huifen ; Pang, Li Mei ; Koh, Wee Luan ; Salleh, Shuhaida Mohamed ; Lakshminarayanan, Rajamani ; Zhou, Lei ; Qiu, Shengxiang ; Pervushin, Konstantin ; Verma, Chandra ; Tan, Donald T. 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Compounds 5c and 6, which contain a hydrophobic xanthone core, lipophilic chains, and cationic amino acids, displayed very promising antimicrobial activity against multidrug-resistant Gram-positive bacteria, including MRSA and VRE, rapid time–kill, avoidance of antibiotic resistance, and low toxicity. The bacterial membrane selectivity of these molecules was comparable to that of several membrane-targeting antibiotics in clinical trials. 5c and 6 were effective in a mouse model of corneal infection by S. aureus and MRSA. Evidence is presented indicating that 5c and 6 target the negatively charged bacterial membrane via a combination of electrostatic and hydrophobic interactions. These results suggest that 5c and 6 have significant promise for combating life-threatening infections.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>25474410</pmid><doi>10.1021/jm501285x</doi><tpages>14</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2015-01, Vol.58 (2), p.739-752 |
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| subjects | Amino Acids - pharmacology Animals Anti-Bacterial Agents - chemical synthesis Anti-Bacterial Agents - pharmacology Cell Membrane - drug effects Drug Resistance, Multiple, Bacterial Gram-Positive Bacterial Infections - drug therapy Magnetic Resonance Spectroscopy Mice Microbial Sensitivity Tests Rabbits Structure-Activity Relationship Unilamellar Liposomes Xanthones - chemical synthesis Xanthones - pharmacology |
| title | Amino Acid Modified Xanthone Derivatives: Novel, Highly Promising Membrane-Active Antimicrobials for Multidrug-Resistant Gram-Positive Bacterial Infections |
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