Structure-Based Design, Synthesis, and A-Site rRNA Cocrystal Complexes of Functionally Novel Aminoglycoside Antibiotics: C2‘ ‘ Ether Analogues of Paromomycin
A series of 2‘ ‘-O-substituted ether analogues of paromomycin were prepared based on new site-selective functionalizations. X-ray cocrystal complexes of several such analogues revealed a new mode of binding in the A-site rRNA, whereby rings I and II adopted the familiar orientation and position prev...
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| Veröffentlicht in: | Journal of medicinal chemistry 2007-05, Vol.50 (10), p.2352-2369 |
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| creator | Hanessian, Stephen Szychowski, Janek Adhikari, Susanta Sekhar Vasquez, Guillermo Kandasamy, Pachamuthu Swayze, Eric E Migawa, Michael T Ranken, Ray François, Boris Wirmer-Bartoschek, Julia Kondo, Jiro Westhof, Eric |
| description | A series of 2‘ ‘-O-substituted ether analogues of paromomycin were prepared based on new site-selective functionalizations. X-ray cocrystal complexes of several such analogues revealed a new mode of binding in the A-site rRNA, whereby rings I and II adopted the familiar orientation and position previously observed with paromomycin, but rings III and IV were oriented differently. With few exceptions, all of the new analogues showed potent inhibitory activity equal or better than paromomycin against a sensitive strain of S. aureus. Single digit μM MIC values were obtained against E. coli, with some of the ether appendages containing polar or basic end groups. Two analogues showed excellent survival rate in a mouse septicemia protection assay. Preliminary histopathological analysis of the kidney showed no overt signs of toxicity, while controls with neomycin and kanamycin were toxic at lower doses. |
| doi_str_mv | 10.1021/jm061200+ |
| format | Article |
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X-ray cocrystal complexes of several such analogues revealed a new mode of binding in the A-site rRNA, whereby rings I and II adopted the familiar orientation and position previously observed with paromomycin, but rings III and IV were oriented differently. With few exceptions, all of the new analogues showed potent inhibitory activity equal or better than paromomycin against a sensitive strain of S. aureus. Single digit μM MIC values were obtained against E. coli, with some of the ether appendages containing polar or basic end groups. Two analogues showed excellent survival rate in a mouse septicemia protection assay. Preliminary histopathological analysis of the kidney showed no overt signs of toxicity, while controls with neomycin and kanamycin were toxic at lower doses.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm061200+</identifier><identifier>PMID: 17458946</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Anti-Bacterial Agents ; Anti-Bacterial Agents - chemical synthesis ; Anti-Bacterial Agents - chemistry ; Anti-Bacterial Agents - pharmacology ; Antibacterial agents ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Binding Sites ; Biochemistry, Molecular Biology ; Biological and medical sciences ; Crystallography, X-Ray ; Drug Design ; Escherichia coli ; Escherichia coli - drug effects ; Ethers ; Ethers - chemical synthesis ; Ethers - chemistry ; Ethers - pharmacology ; Female ; General aspects ; Life Sciences ; Medical sciences ; Mice ; Mice, Inbred BALB C ; Microbial Sensitivity Tests ; Models, Molecular ; Molecular Structure ; Paromomycin ; Paromomycin - analogs & derivatives ; Paromomycin - chemical synthesis ; Paromomycin - chemistry ; Paromomycin - pharmacology ; Pharmacology. Drug treatments ; RNA, Ribosomal ; RNA, Ribosomal - chemistry ; Sepsis ; Sepsis - prevention & control ; Staphylococcal Infections ; Staphylococcal Infections - prevention & control ; Staphylococcus aureus ; Staphylococcus aureus - drug effects ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2007-05, Vol.50 (10), p.2352-2369</ispartof><rights>Copyright © 2007 American Chemical Society</rights><rights>2007 INIST-CNRS</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a443t-6b31155c02b59be48cf4d06fe84e87c165958fa89a1d6d46d481ab3ba95b69d63</citedby><cites>FETCH-LOGICAL-a443t-6b31155c02b59be48cf4d06fe84e87c165958fa89a1d6d46d481ab3ba95b69d63</cites><orcidid>0000-0002-6172-5422</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm061200+$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm061200+$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,780,784,885,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18767484$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17458946$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-00167553$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Hanessian, Stephen</creatorcontrib><creatorcontrib>Szychowski, Janek</creatorcontrib><creatorcontrib>Adhikari, Susanta Sekhar</creatorcontrib><creatorcontrib>Vasquez, Guillermo</creatorcontrib><creatorcontrib>Kandasamy, Pachamuthu</creatorcontrib><creatorcontrib>Swayze, Eric E</creatorcontrib><creatorcontrib>Migawa, Michael T</creatorcontrib><creatorcontrib>Ranken, Ray</creatorcontrib><creatorcontrib>François, Boris</creatorcontrib><creatorcontrib>Wirmer-Bartoschek, Julia</creatorcontrib><creatorcontrib>Kondo, Jiro</creatorcontrib><creatorcontrib>Westhof, Eric</creatorcontrib><title>Structure-Based Design, Synthesis, and A-Site rRNA Cocrystal Complexes of Functionally Novel Aminoglycoside Antibiotics: C2‘ ‘ Ether Analogues of Paromomycin</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A series of 2‘ ‘-O-substituted ether analogues of paromomycin were prepared based on new site-selective functionalizations. X-ray cocrystal complexes of several such analogues revealed a new mode of binding in the A-site rRNA, whereby rings I and II adopted the familiar orientation and position previously observed with paromomycin, but rings III and IV were oriented differently. With few exceptions, all of the new analogues showed potent inhibitory activity equal or better than paromomycin against a sensitive strain of S. aureus. Single digit μM MIC values were obtained against E. coli, with some of the ether appendages containing polar or basic end groups. Two analogues showed excellent survival rate in a mouse septicemia protection assay. Preliminary histopathological analysis of the kidney showed no overt signs of toxicity, while controls with neomycin and kanamycin were toxic at lower doses.</description><subject>Animals</subject><subject>Anti-Bacterial Agents</subject><subject>Anti-Bacterial Agents - chemical synthesis</subject><subject>Anti-Bacterial Agents - chemistry</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Antibacterial agents</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Binding Sites</subject><subject>Biochemistry, Molecular Biology</subject><subject>Biological and medical sciences</subject><subject>Crystallography, X-Ray</subject><subject>Drug Design</subject><subject>Escherichia coli</subject><subject>Escherichia coli - drug effects</subject><subject>Ethers</subject><subject>Ethers - chemical synthesis</subject><subject>Ethers - chemistry</subject><subject>Ethers - pharmacology</subject><subject>Female</subject><subject>General aspects</subject><subject>Life Sciences</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Microbial Sensitivity Tests</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Paromomycin</subject><subject>Paromomycin - analogs & derivatives</subject><subject>Paromomycin - chemical synthesis</subject><subject>Paromomycin - chemistry</subject><subject>Paromomycin - pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>RNA, Ribosomal</subject><subject>RNA, Ribosomal - chemistry</subject><subject>Sepsis</subject><subject>Sepsis - prevention & control</subject><subject>Staphylococcal Infections</subject><subject>Staphylococcal Infections - prevention & control</subject><subject>Staphylococcus aureus</subject><subject>Staphylococcus aureus - drug effects</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpl0UFu1DAUBuAIgWgpLLgA8gIQiAbs2HEcdmHotIihjJiythzHmXpw4sF2qmbXLTfgBBysJ8FVhnaBZNlP9qffT3pJ8hTBtwhm6N2mgxRlEL65l-yjPIMpYZDcT_YhzLI0oxneSx55v4EQYpThh8keKkjOSkL3kz-r4AYZBqfSD8KrBnxUXq_7Q7Aa-3Aea38IRN-AKl3poID7dlqBmZVu9EGYWHVboy6VB7YF86GXQdteGDOCU3uhDKg63du1GaX1ulGg6oOutQ1a-vfXV7_ALLu--h2LuIOj-JuLQhi7HqbApXC2s90odf84edAK49WT3XmQfJ8fnc1O0sXX40-zapEKQnBIaY0RynMJszova0WYbEkDaasYUayQiOZlzlrBSoEa2pC4GBI1rkWZ17RsKD5IXk-558LwrdOdcCO3QvOTasFv7iBEtMhzfIGifTnZrbM_Y8uBd9pLZYzolR08R2WBMWNFhK8mKJ313qn2NhlBfjNA_m-AkT7bZQ51p5o7uBtYBC92QHgpTOtEL7W_c6ygBWEkunRy2gd1efsu3A9OC1zk_Gy54svPZTH_cgz5IvrnkxfS840dXByE_7-_v0WKwQk</recordid><startdate>20070517</startdate><enddate>20070517</enddate><creator>Hanessian, Stephen</creator><creator>Szychowski, Janek</creator><creator>Adhikari, Susanta Sekhar</creator><creator>Vasquez, Guillermo</creator><creator>Kandasamy, Pachamuthu</creator><creator>Swayze, Eric E</creator><creator>Migawa, Michael T</creator><creator>Ranken, Ray</creator><creator>François, Boris</creator><creator>Wirmer-Bartoschek, Julia</creator><creator>Kondo, Jiro</creator><creator>Westhof, Eric</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-6172-5422</orcidid></search><sort><creationdate>20070517</creationdate><title>Structure-Based Design, Synthesis, and A-Site rRNA Cocrystal Complexes of Functionally Novel Aminoglycoside Antibiotics: C2‘ ‘ Ether Analogues of Paromomycin</title><author>Hanessian, Stephen ; Szychowski, Janek ; Adhikari, Susanta Sekhar ; Vasquez, Guillermo ; Kandasamy, Pachamuthu ; Swayze, Eric E ; Migawa, Michael T ; Ranken, Ray ; François, Boris ; Wirmer-Bartoschek, Julia ; Kondo, Jiro ; Westhof, Eric</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a443t-6b31155c02b59be48cf4d06fe84e87c165958fa89a1d6d46d481ab3ba95b69d63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Animals</topic><topic>Anti-Bacterial Agents</topic><topic>Anti-Bacterial Agents - chemical synthesis</topic><topic>Anti-Bacterial Agents - chemistry</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Antibacterial agents</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Binding Sites</topic><topic>Biochemistry, Molecular Biology</topic><topic>Biological and medical sciences</topic><topic>Crystallography, X-Ray</topic><topic>Drug Design</topic><topic>Escherichia coli</topic><topic>Escherichia coli - drug effects</topic><topic>Ethers</topic><topic>Ethers - chemical synthesis</topic><topic>Ethers - chemistry</topic><topic>Ethers - pharmacology</topic><topic>Female</topic><topic>General aspects</topic><topic>Life Sciences</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Microbial Sensitivity Tests</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Paromomycin</topic><topic>Paromomycin - analogs & derivatives</topic><topic>Paromomycin - chemical synthesis</topic><topic>Paromomycin - chemistry</topic><topic>Paromomycin - pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>RNA, Ribosomal</topic><topic>RNA, Ribosomal - chemistry</topic><topic>Sepsis</topic><topic>Sepsis - prevention & control</topic><topic>Staphylococcal Infections</topic><topic>Staphylococcal Infections - prevention & control</topic><topic>Staphylococcus aureus</topic><topic>Staphylococcus aureus - drug effects</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hanessian, Stephen</creatorcontrib><creatorcontrib>Szychowski, Janek</creatorcontrib><creatorcontrib>Adhikari, Susanta Sekhar</creatorcontrib><creatorcontrib>Vasquez, Guillermo</creatorcontrib><creatorcontrib>Kandasamy, Pachamuthu</creatorcontrib><creatorcontrib>Swayze, Eric E</creatorcontrib><creatorcontrib>Migawa, Michael T</creatorcontrib><creatorcontrib>Ranken, Ray</creatorcontrib><creatorcontrib>François, Boris</creatorcontrib><creatorcontrib>Wirmer-Bartoschek, Julia</creatorcontrib><creatorcontrib>Kondo, Jiro</creatorcontrib><creatorcontrib>Westhof, Eric</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hanessian, Stephen</au><au>Szychowski, Janek</au><au>Adhikari, Susanta Sekhar</au><au>Vasquez, Guillermo</au><au>Kandasamy, Pachamuthu</au><au>Swayze, Eric E</au><au>Migawa, Michael T</au><au>Ranken, Ray</au><au>François, Boris</au><au>Wirmer-Bartoschek, Julia</au><au>Kondo, Jiro</au><au>Westhof, Eric</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure-Based Design, Synthesis, and A-Site rRNA Cocrystal Complexes of Functionally Novel Aminoglycoside Antibiotics: C2‘ ‘ Ether Analogues of Paromomycin</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2007-05-17</date><risdate>2007</risdate><volume>50</volume><issue>10</issue><spage>2352</spage><epage>2369</epage><pages>2352-2369</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A series of 2‘ ‘-O-substituted ether analogues of paromomycin were prepared based on new site-selective functionalizations. X-ray cocrystal complexes of several such analogues revealed a new mode of binding in the A-site rRNA, whereby rings I and II adopted the familiar orientation and position previously observed with paromomycin, but rings III and IV were oriented differently. With few exceptions, all of the new analogues showed potent inhibitory activity equal or better than paromomycin against a sensitive strain of S. aureus. Single digit μM MIC values were obtained against E. coli, with some of the ether appendages containing polar or basic end groups. Two analogues showed excellent survival rate in a mouse septicemia protection assay. Preliminary histopathological analysis of the kidney showed no overt signs of toxicity, while controls with neomycin and kanamycin were toxic at lower doses.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>17458946</pmid><doi>10.1021/jm061200+</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0002-6172-5422</orcidid></addata></record> |
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| source | MEDLINE; ACS Publications |
| subjects | Animals Anti-Bacterial Agents Anti-Bacterial Agents - chemical synthesis Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Antibacterial agents Antibiotics. Antiinfectious agents. Antiparasitic agents Binding Sites Biochemistry, Molecular Biology Biological and medical sciences Crystallography, X-Ray Drug Design Escherichia coli Escherichia coli - drug effects Ethers Ethers - chemical synthesis Ethers - chemistry Ethers - pharmacology Female General aspects Life Sciences Medical sciences Mice Mice, Inbred BALB C Microbial Sensitivity Tests Models, Molecular Molecular Structure Paromomycin Paromomycin - analogs & derivatives Paromomycin - chemical synthesis Paromomycin - chemistry Paromomycin - pharmacology Pharmacology. Drug treatments RNA, Ribosomal RNA, Ribosomal - chemistry Sepsis Sepsis - prevention & control Staphylococcal Infections Staphylococcal Infections - prevention & control Staphylococcus aureus Staphylococcus aureus - drug effects Structure-Activity Relationship |
| title | Structure-Based Design, Synthesis, and A-Site rRNA Cocrystal Complexes of Functionally Novel Aminoglycoside Antibiotics: C2‘ ‘ Ether Analogues of Paromomycin |
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