Combinatorial Libraries As a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE Pathogens
Mixture based synthetic combinatorial libraries offer a tremendous enhancement for the rate of drug discovery, allowing the activity of millions of compounds to be assessed through the testing of exponentially fewer samples. In this study, we used a scaffold-ranking library to screen 37 different li...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 2015-04, Vol.58 (8), p.3340-3355 |
|---|---|
| Hauptverfasser: | , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 3355 |
|---|---|
| container_issue | 8 |
| container_start_page | 3340 |
| container_title | Journal of medicinal chemistry |
| container_volume | 58 |
| creator | Fleeman, Renee LaVoi, Travis M Santos, Radleigh G Morales, Angela Nefzi, Adel Welmaker, Gregory S Medina-Franco, José L Giulianotti, Marc A Houghten, Richard A Shaw, Lindsey N |
| description | Mixture based synthetic combinatorial libraries offer a tremendous enhancement for the rate of drug discovery, allowing the activity of millions of compounds to be assessed through the testing of exponentially fewer samples. In this study, we used a scaffold-ranking library to screen 37 different libraries for antibacterial activity against the ESKAPE pathogens. Each library contained between 10000 and 750000 structural analogues for a total of >6 million compounds. From this, we identified a bis-cyclic guanidine library that displayed strong antibacterial activity. A positional scanning library for these compounds was developed and used to identify the most effective functional groups at each variant position. Individual compounds were synthesized that were broadly active against all ESKAPE organisms at concentrations |
| doi_str_mv | 10.1021/jm501628s |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8982266</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1675871897</sourcerecordid><originalsourceid>FETCH-LOGICAL-a405t-ae2a8bc7144bb8a213d14c3e58082a93a46b364a449767506f29b213f3aa541d3</originalsourceid><addsrcrecordid>eNptkU1r3DAQhkVoSLZpDvkDRZdCC3WqL9vypeButknI0gayOYuRV97VYltbSQ7klp9eNZssLfQ0A_PwzDAvQmeUnFPC6JdNnxNaMBkO0ITmjGRCEvEGTQhhLGMF48fobQgbQginjB-hY5aXklQyn6Cnqeu1HSA6b6HDc6s9eGsCrgMGvHCuw63zOK4NvrChcQ_GP2LX4h-p6z7jb97BMrvbmib6scf1EK2GJppnWb0yQwx4AX5loh1Wz5bZ3U19O8O3ENcuzcM7dNhCF8zpSz1B999ni-lVNv95eT2t5xkIkscMDAOpm5IKobUERvmSioabXBLJoOIgCs0LAUJUZVHmpGhZpRPVcoBc0CU_QV933u2oe7Ns0mkeOrX1tgf_qBxY9e9ksGu1cg9KVpKxokiCjy8C736NJkTVp4eYroPBuDEomtbKksqqTOinHdp4F4I37X4NJepPYmqfWGLf_33XnnyNKAEfdgA0QW3c6If0pv-IfgPq6Z4f</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1675871897</pqid></control><display><type>article</type><title>Combinatorial Libraries As a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE Pathogens</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>Fleeman, Renee ; LaVoi, Travis M ; Santos, Radleigh G ; Morales, Angela ; Nefzi, Adel ; Welmaker, Gregory S ; Medina-Franco, José L ; Giulianotti, Marc A ; Houghten, Richard A ; Shaw, Lindsey N</creator><creatorcontrib>Fleeman, Renee ; LaVoi, Travis M ; Santos, Radleigh G ; Morales, Angela ; Nefzi, Adel ; Welmaker, Gregory S ; Medina-Franco, José L ; Giulianotti, Marc A ; Houghten, Richard A ; Shaw, Lindsey N</creatorcontrib><description>Mixture based synthetic combinatorial libraries offer a tremendous enhancement for the rate of drug discovery, allowing the activity of millions of compounds to be assessed through the testing of exponentially fewer samples. In this study, we used a scaffold-ranking library to screen 37 different libraries for antibacterial activity against the ESKAPE pathogens. Each library contained between 10000 and 750000 structural analogues for a total of >6 million compounds. From this, we identified a bis-cyclic guanidine library that displayed strong antibacterial activity. A positional scanning library for these compounds was developed and used to identify the most effective functional groups at each variant position. Individual compounds were synthesized that were broadly active against all ESKAPE organisms at concentrations <2 μM. In addition, these compounds were bactericidal, had antibiofilm effects, showed limited potential for the development of resistance, and displayed almost no toxicity when tested against human lung cells and erythrocytes. Using a murine model of peritonitis, we also demonstrate that these agents are highly efficacious in vivo.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm501628s</identifier><identifier>PMID: 25780985</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Anti-Bacterial Agents - chemistry ; Anti-Bacterial Agents - pharmacology ; Anti-Bacterial Agents - therapeutic use ; Bacteria - drug effects ; Bacterial Infections - drug therapy ; Cell Line ; Drug Discovery ; Guanidines - chemistry ; Guanidines - pharmacology ; Humans ; Mice ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - pharmacology ; Small Molecule Libraries - therapeutic use ; Staphylococcal Infections - drug therapy ; Staphylococcus aureus - drug effects</subject><ispartof>Journal of medicinal chemistry, 2015-04, Vol.58 (8), p.3340-3355</ispartof><rights>Copyright © American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a405t-ae2a8bc7144bb8a213d14c3e58082a93a46b364a449767506f29b213f3aa541d3</citedby><cites>FETCH-LOGICAL-a405t-ae2a8bc7144bb8a213d14c3e58082a93a46b364a449767506f29b213f3aa541d3</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/jm501628s$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm501628s$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,780,784,885,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25780985$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fleeman, Renee</creatorcontrib><creatorcontrib>LaVoi, Travis M</creatorcontrib><creatorcontrib>Santos, Radleigh G</creatorcontrib><creatorcontrib>Morales, Angela</creatorcontrib><creatorcontrib>Nefzi, Adel</creatorcontrib><creatorcontrib>Welmaker, Gregory S</creatorcontrib><creatorcontrib>Medina-Franco, José L</creatorcontrib><creatorcontrib>Giulianotti, Marc A</creatorcontrib><creatorcontrib>Houghten, Richard A</creatorcontrib><creatorcontrib>Shaw, Lindsey N</creatorcontrib><title>Combinatorial Libraries As a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE Pathogens</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Mixture based synthetic combinatorial libraries offer a tremendous enhancement for the rate of drug discovery, allowing the activity of millions of compounds to be assessed through the testing of exponentially fewer samples. In this study, we used a scaffold-ranking library to screen 37 different libraries for antibacterial activity against the ESKAPE pathogens. Each library contained between 10000 and 750000 structural analogues for a total of >6 million compounds. From this, we identified a bis-cyclic guanidine library that displayed strong antibacterial activity. A positional scanning library for these compounds was developed and used to identify the most effective functional groups at each variant position. Individual compounds were synthesized that were broadly active against all ESKAPE organisms at concentrations <2 μM. In addition, these compounds were bactericidal, had antibiofilm effects, showed limited potential for the development of resistance, and displayed almost no toxicity when tested against human lung cells and erythrocytes. Using a murine model of peritonitis, we also demonstrate that these agents are highly efficacious in vivo.</description><subject>Animals</subject><subject>Anti-Bacterial Agents - chemistry</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Anti-Bacterial Agents - therapeutic use</subject><subject>Bacteria - drug effects</subject><subject>Bacterial Infections - drug therapy</subject><subject>Cell Line</subject><subject>Drug Discovery</subject><subject>Guanidines - chemistry</subject><subject>Guanidines - pharmacology</subject><subject>Humans</subject><subject>Mice</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - pharmacology</subject><subject>Small Molecule Libraries - therapeutic use</subject><subject>Staphylococcal Infections - drug therapy</subject><subject>Staphylococcus aureus - drug effects</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>eNptkU1r3DAQhkVoSLZpDvkDRZdCC3WqL9vypeButknI0gayOYuRV97VYltbSQ7klp9eNZssLfQ0A_PwzDAvQmeUnFPC6JdNnxNaMBkO0ITmjGRCEvEGTQhhLGMF48fobQgbQginjB-hY5aXklQyn6Cnqeu1HSA6b6HDc6s9eGsCrgMGvHCuw63zOK4NvrChcQ_GP2LX4h-p6z7jb97BMrvbmib6scf1EK2GJppnWb0yQwx4AX5loh1Wz5bZ3U19O8O3ENcuzcM7dNhCF8zpSz1B999ni-lVNv95eT2t5xkIkscMDAOpm5IKobUERvmSioabXBLJoOIgCs0LAUJUZVHmpGhZpRPVcoBc0CU_QV933u2oe7Ns0mkeOrX1tgf_qBxY9e9ksGu1cg9KVpKxokiCjy8C736NJkTVp4eYroPBuDEomtbKksqqTOinHdp4F4I37X4NJepPYmqfWGLf_33XnnyNKAEfdgA0QW3c6If0pv-IfgPq6Z4f</recordid><startdate>20150423</startdate><enddate>20150423</enddate><creator>Fleeman, Renee</creator><creator>LaVoi, Travis M</creator><creator>Santos, Radleigh G</creator><creator>Morales, Angela</creator><creator>Nefzi, Adel</creator><creator>Welmaker, Gregory S</creator><creator>Medina-Franco, José L</creator><creator>Giulianotti, Marc A</creator><creator>Houghten, Richard A</creator><creator>Shaw, Lindsey N</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><scope>5PM</scope></search><sort><creationdate>20150423</creationdate><title>Combinatorial Libraries As a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE Pathogens</title><author>Fleeman, Renee ; LaVoi, Travis M ; Santos, Radleigh G ; Morales, Angela ; Nefzi, Adel ; Welmaker, Gregory S ; Medina-Franco, José L ; Giulianotti, Marc A ; Houghten, Richard A ; Shaw, Lindsey N</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a405t-ae2a8bc7144bb8a213d14c3e58082a93a46b364a449767506f29b213f3aa541d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Anti-Bacterial Agents - chemistry</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Anti-Bacterial Agents - therapeutic use</topic><topic>Bacteria - drug effects</topic><topic>Bacterial Infections - drug therapy</topic><topic>Cell Line</topic><topic>Drug Discovery</topic><topic>Guanidines - chemistry</topic><topic>Guanidines - pharmacology</topic><topic>Humans</topic><topic>Mice</topic><topic>Small Molecule Libraries - chemistry</topic><topic>Small Molecule Libraries - pharmacology</topic><topic>Small Molecule Libraries - therapeutic use</topic><topic>Staphylococcal Infections - drug therapy</topic><topic>Staphylococcus aureus - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fleeman, Renee</creatorcontrib><creatorcontrib>LaVoi, Travis M</creatorcontrib><creatorcontrib>Santos, Radleigh G</creatorcontrib><creatorcontrib>Morales, Angela</creatorcontrib><creatorcontrib>Nefzi, Adel</creatorcontrib><creatorcontrib>Welmaker, Gregory S</creatorcontrib><creatorcontrib>Medina-Franco, José L</creatorcontrib><creatorcontrib>Giulianotti, Marc A</creatorcontrib><creatorcontrib>Houghten, Richard A</creatorcontrib><creatorcontrib>Shaw, Lindsey N</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fleeman, Renee</au><au>LaVoi, Travis M</au><au>Santos, Radleigh G</au><au>Morales, Angela</au><au>Nefzi, Adel</au><au>Welmaker, Gregory S</au><au>Medina-Franco, José L</au><au>Giulianotti, Marc A</au><au>Houghten, Richard A</au><au>Shaw, Lindsey N</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Combinatorial Libraries As a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE Pathogens</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2015-04-23</date><risdate>2015</risdate><volume>58</volume><issue>8</issue><spage>3340</spage><epage>3355</epage><pages>3340-3355</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Mixture based synthetic combinatorial libraries offer a tremendous enhancement for the rate of drug discovery, allowing the activity of millions of compounds to be assessed through the testing of exponentially fewer samples. In this study, we used a scaffold-ranking library to screen 37 different libraries for antibacterial activity against the ESKAPE pathogens. Each library contained between 10000 and 750000 structural analogues for a total of >6 million compounds. From this, we identified a bis-cyclic guanidine library that displayed strong antibacterial activity. A positional scanning library for these compounds was developed and used to identify the most effective functional groups at each variant position. Individual compounds were synthesized that were broadly active against all ESKAPE organisms at concentrations <2 μM. In addition, these compounds were bactericidal, had antibiofilm effects, showed limited potential for the development of resistance, and displayed almost no toxicity when tested against human lung cells and erythrocytes. Using a murine model of peritonitis, we also demonstrate that these agents are highly efficacious in vivo.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>25780985</pmid><doi>10.1021/jm501628s</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2015-04, Vol.58 (8), p.3340-3355 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8982266 |
| source | MEDLINE; American Chemical Society Journals |
| subjects | Animals Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Anti-Bacterial Agents - therapeutic use Bacteria - drug effects Bacterial Infections - drug therapy Cell Line Drug Discovery Guanidines - chemistry Guanidines - pharmacology Humans Mice Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Small Molecule Libraries - therapeutic use Staphylococcal Infections - drug therapy Staphylococcus aureus - drug effects |
| title | Combinatorial Libraries As a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE Pathogens |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-03T01%3A30%3A58IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Combinatorial%20Libraries%20As%20a%20Tool%20for%20the%20Discovery%20of%20Novel,%20Broad-Spectrum%20Antibacterial%20Agents%20Targeting%20the%20ESKAPE%20Pathogens&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Fleeman,%20Renee&rft.date=2015-04-23&rft.volume=58&rft.issue=8&rft.spage=3340&rft.epage=3355&rft.pages=3340-3355&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/jm501628s&rft_dat=%3Cproquest_pubme%3E1675871897%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1675871897&rft_id=info:pmid/25780985&rfr_iscdi=true |