Multicopy Suppressors for Novel Antibacterial Compounds Reveal Targets and Drug Efflux Susceptibility
Gene dosage has frequently been exploited to select for genetic interactions between a particular mutant and clones from a random genomic library at high copy. We report here the first use of multicopy suppression as a forward genetic method to determine cellular targets and potential resistance mec...
Gespeichert in:
| Veröffentlicht in: | Chemistry & biology 2004-10, Vol.11 (10), p.1423-1430 |
|---|---|
| Hauptverfasser: | , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1430 |
|---|---|
| container_issue | 10 |
| container_start_page | 1423 |
| container_title | Chemistry & biology |
| container_volume | 11 |
| creator | Li, Xiaoming Zolli-Juran, Michela Cechetto, Jonathan D. Daigle, Denis M. Wright, Gerard D. Brown, Eric D. |
| description | Gene dosage has frequently been exploited to select for genetic interactions between a particular mutant and clones from a random genomic library at high copy. We report here the first use of multicopy suppression as a forward genetic method to determine cellular targets and potential resistance mechanisms for novel antibacterial compounds identified through high-throughput screening. A screen of 8640 small molecules for growth inhibition of a hyperpermeable strain of
Escherichia coli led to the identification of 49 leads for suppressor selection from clones harboring an
E. coli genomic library. The majority of suppressors were found to encode the multidrug efflux pump AcrB, indicating that those compounds were substrates for efflux. Two leads, which produced clones containing the gene
folA, encoding dihydrofolate reductase (DHFR), proved to target DHFR in vivo and were competitive inhibitors in vitro. |
| doi_str_mv | 10.1016/j.chembiol.2004.08.014 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_66976618</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S1074552104002492</els_id><sourcerecordid>66976618</sourcerecordid><originalsourceid>FETCH-LOGICAL-c443t-7eb6f409735f95917dcd8e4dd7e658a3ae4596a203cac826a4c4b949729a19163</originalsourceid><addsrcrecordid>eNqFkctO3DAUhq2KqlzKKyCv2CW1E8exd6DhUiSgUgtry7FPwCMnDnYyYt6-RjNVl6zO0dH3n9uP0BklJSWU_1iX5hWGzgVfVoSwkoiSUPYFHVHRyoLWhB7knLSsaJqKHqLjlNaEECok_4YOacOEpFweIXhY_OxMmLb4zzJNEVIKMeE-RPwYNuDx5Ti7TpsZotMer8IwhWW0Cf-GDeTCk44vMCesR4uv4vKCr_veL--5WTIwZanzbt5-R1977ROc7uMJer65flr9LO5_3d6tLu8Lw1g9Fy10vGdEtnXTy0bS1horgFnbAm-ErjWwRnJdkdpoIyqumWGdZLKtpKb5nvoEne_6TjG8LZBmNbi8h_d6hLAkxblsOafiU5BKSZuqrjLId6CJIaUIvZqiG3TcKkrUhxNqrf45oT6cUESo7EQWnu0nLN0A9r9s__oMXOwAyA_ZOIgqGQejAesimFnZ4D6b8Reg0567</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>19915232</pqid></control><display><type>article</type><title>Multicopy Suppressors for Novel Antibacterial Compounds Reveal Targets and Drug Efflux Susceptibility</title><source>MEDLINE</source><source>Cell Press Free Archives</source><source>Access via ScienceDirect (Elsevier)</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Free Full-Text Journals in Chemistry</source><creator>Li, Xiaoming ; Zolli-Juran, Michela ; Cechetto, Jonathan D. ; Daigle, Denis M. ; Wright, Gerard D. ; Brown, Eric D.</creator><creatorcontrib>Li, Xiaoming ; Zolli-Juran, Michela ; Cechetto, Jonathan D. ; Daigle, Denis M. ; Wright, Gerard D. ; Brown, Eric D.</creatorcontrib><description>Gene dosage has frequently been exploited to select for genetic interactions between a particular mutant and clones from a random genomic library at high copy. We report here the first use of multicopy suppression as a forward genetic method to determine cellular targets and potential resistance mechanisms for novel antibacterial compounds identified through high-throughput screening. A screen of 8640 small molecules for growth inhibition of a hyperpermeable strain of
Escherichia coli led to the identification of 49 leads for suppressor selection from clones harboring an
E. coli genomic library. The majority of suppressors were found to encode the multidrug efflux pump AcrB, indicating that those compounds were substrates for efflux. Two leads, which produced clones containing the gene
folA, encoding dihydrofolate reductase (DHFR), proved to target DHFR in vivo and were competitive inhibitors in vitro.</description><identifier>ISSN: 1074-5521</identifier><identifier>EISSN: 1879-1301</identifier><identifier>DOI: 10.1016/j.chembiol.2004.08.014</identifier><identifier>PMID: 15489169</identifier><language>eng</language><publisher>United States: Elsevier Ltd</publisher><subject>Anti-Bacterial Agents - administration & dosage ; Anti-Bacterial Agents - chemistry ; Drug Delivery Systems - methods ; Drug Resistance, Bacterial - genetics ; Escherichia coli ; Escherichia coli - drug effects ; Escherichia coli - enzymology ; Escherichia coli - genetics ; Escherichia coli - growth & development ; Gene Dosage ; Genome, Bacterial ; Genomic Library ; Growth Inhibitors - administration & dosage ; Growth Inhibitors - chemistry ; Microbial Sensitivity Tests - statistics & numerical data ; Tetrahydrofolate Dehydrogenase - biosynthesis ; Tetrahydrofolate Dehydrogenase - physiology</subject><ispartof>Chemistry & biology, 2004-10, Vol.11 (10), p.1423-1430</ispartof><rights>2004 Elsevier Ltd</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-7eb6f409735f95917dcd8e4dd7e658a3ae4596a203cac826a4c4b949729a19163</citedby><cites>FETCH-LOGICAL-c443t-7eb6f409735f95917dcd8e4dd7e658a3ae4596a203cac826a4c4b949729a19163</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.chembiol.2004.08.014$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>315,782,786,3554,27933,27934,46004</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15489169$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Xiaoming</creatorcontrib><creatorcontrib>Zolli-Juran, Michela</creatorcontrib><creatorcontrib>Cechetto, Jonathan D.</creatorcontrib><creatorcontrib>Daigle, Denis M.</creatorcontrib><creatorcontrib>Wright, Gerard D.</creatorcontrib><creatorcontrib>Brown, Eric D.</creatorcontrib><title>Multicopy Suppressors for Novel Antibacterial Compounds Reveal Targets and Drug Efflux Susceptibility</title><title>Chemistry & biology</title><addtitle>Chem Biol</addtitle><description>Gene dosage has frequently been exploited to select for genetic interactions between a particular mutant and clones from a random genomic library at high copy. We report here the first use of multicopy suppression as a forward genetic method to determine cellular targets and potential resistance mechanisms for novel antibacterial compounds identified through high-throughput screening. A screen of 8640 small molecules for growth inhibition of a hyperpermeable strain of
Escherichia coli led to the identification of 49 leads for suppressor selection from clones harboring an
E. coli genomic library. The majority of suppressors were found to encode the multidrug efflux pump AcrB, indicating that those compounds were substrates for efflux. Two leads, which produced clones containing the gene
folA, encoding dihydrofolate reductase (DHFR), proved to target DHFR in vivo and were competitive inhibitors in vitro.</description><subject>Anti-Bacterial Agents - administration & dosage</subject><subject>Anti-Bacterial Agents - chemistry</subject><subject>Drug Delivery Systems - methods</subject><subject>Drug Resistance, Bacterial - genetics</subject><subject>Escherichia coli</subject><subject>Escherichia coli - drug effects</subject><subject>Escherichia coli - enzymology</subject><subject>Escherichia coli - genetics</subject><subject>Escherichia coli - growth & development</subject><subject>Gene Dosage</subject><subject>Genome, Bacterial</subject><subject>Genomic Library</subject><subject>Growth Inhibitors - administration & dosage</subject><subject>Growth Inhibitors - chemistry</subject><subject>Microbial Sensitivity Tests - statistics & numerical data</subject><subject>Tetrahydrofolate Dehydrogenase - biosynthesis</subject><subject>Tetrahydrofolate Dehydrogenase - physiology</subject><issn>1074-5521</issn><issn>1879-1301</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkctO3DAUhq2KqlzKKyCv2CW1E8exd6DhUiSgUgtry7FPwCMnDnYyYt6-RjNVl6zO0dH3n9uP0BklJSWU_1iX5hWGzgVfVoSwkoiSUPYFHVHRyoLWhB7knLSsaJqKHqLjlNaEECok_4YOacOEpFweIXhY_OxMmLb4zzJNEVIKMeE-RPwYNuDx5Ti7TpsZotMer8IwhWW0Cf-GDeTCk44vMCesR4uv4vKCr_veL--5WTIwZanzbt5-R1977ROc7uMJer65flr9LO5_3d6tLu8Lw1g9Fy10vGdEtnXTy0bS1horgFnbAm-ErjWwRnJdkdpoIyqumWGdZLKtpKb5nvoEne_6TjG8LZBmNbi8h_d6hLAkxblsOafiU5BKSZuqrjLId6CJIaUIvZqiG3TcKkrUhxNqrf45oT6cUESo7EQWnu0nLN0A9r9s__oMXOwAyA_ZOIgqGQejAesimFnZ4D6b8Reg0567</recordid><startdate>20041001</startdate><enddate>20041001</enddate><creator>Li, Xiaoming</creator><creator>Zolli-Juran, Michela</creator><creator>Cechetto, Jonathan D.</creator><creator>Daigle, Denis M.</creator><creator>Wright, Gerard D.</creator><creator>Brown, Eric D.</creator><general>Elsevier Ltd</general><scope>6I.</scope><scope>AAFTH</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>7QL</scope><scope>7QO</scope><scope>7T7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20041001</creationdate><title>Multicopy Suppressors for Novel Antibacterial Compounds Reveal Targets and Drug Efflux Susceptibility</title><author>Li, Xiaoming ; Zolli-Juran, Michela ; Cechetto, Jonathan D. ; Daigle, Denis M. ; Wright, Gerard D. ; Brown, Eric D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c443t-7eb6f409735f95917dcd8e4dd7e658a3ae4596a203cac826a4c4b949729a19163</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Anti-Bacterial Agents - administration & dosage</topic><topic>Anti-Bacterial Agents - chemistry</topic><topic>Drug Delivery Systems - methods</topic><topic>Drug Resistance, Bacterial - genetics</topic><topic>Escherichia coli</topic><topic>Escherichia coli - drug effects</topic><topic>Escherichia coli - enzymology</topic><topic>Escherichia coli - genetics</topic><topic>Escherichia coli - growth & development</topic><topic>Gene Dosage</topic><topic>Genome, Bacterial</topic><topic>Genomic Library</topic><topic>Growth Inhibitors - administration & dosage</topic><topic>Growth Inhibitors - chemistry</topic><topic>Microbial Sensitivity Tests - statistics & numerical data</topic><topic>Tetrahydrofolate Dehydrogenase - biosynthesis</topic><topic>Tetrahydrofolate Dehydrogenase - physiology</topic><toplevel>online_resources</toplevel><creatorcontrib>Li, Xiaoming</creatorcontrib><creatorcontrib>Zolli-Juran, Michela</creatorcontrib><creatorcontrib>Cechetto, Jonathan D.</creatorcontrib><creatorcontrib>Daigle, Denis M.</creatorcontrib><creatorcontrib>Wright, Gerard D.</creatorcontrib><creatorcontrib>Brown, Eric D.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Chemistry & biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Xiaoming</au><au>Zolli-Juran, Michela</au><au>Cechetto, Jonathan D.</au><au>Daigle, Denis M.</au><au>Wright, Gerard D.</au><au>Brown, Eric D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Multicopy Suppressors for Novel Antibacterial Compounds Reveal Targets and Drug Efflux Susceptibility</atitle><jtitle>Chemistry & biology</jtitle><addtitle>Chem Biol</addtitle><date>2004-10-01</date><risdate>2004</risdate><volume>11</volume><issue>10</issue><spage>1423</spage><epage>1430</epage><pages>1423-1430</pages><issn>1074-5521</issn><eissn>1879-1301</eissn><abstract>Gene dosage has frequently been exploited to select for genetic interactions between a particular mutant and clones from a random genomic library at high copy. We report here the first use of multicopy suppression as a forward genetic method to determine cellular targets and potential resistance mechanisms for novel antibacterial compounds identified through high-throughput screening. A screen of 8640 small molecules for growth inhibition of a hyperpermeable strain of
Escherichia coli led to the identification of 49 leads for suppressor selection from clones harboring an
E. coli genomic library. The majority of suppressors were found to encode the multidrug efflux pump AcrB, indicating that those compounds were substrates for efflux. Two leads, which produced clones containing the gene
folA, encoding dihydrofolate reductase (DHFR), proved to target DHFR in vivo and were competitive inhibitors in vitro.</abstract><cop>United States</cop><pub>Elsevier Ltd</pub><pmid>15489169</pmid><doi>10.1016/j.chembiol.2004.08.014</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1074-5521 |
| ispartof | Chemistry & biology, 2004-10, Vol.11 (10), p.1423-1430 |
| issn | 1074-5521 1879-1301 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_66976618 |
| source | MEDLINE; Cell Press Free Archives; Access via ScienceDirect (Elsevier); Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Free Full-Text Journals in Chemistry |
| subjects | Anti-Bacterial Agents - administration & dosage Anti-Bacterial Agents - chemistry Drug Delivery Systems - methods Drug Resistance, Bacterial - genetics Escherichia coli Escherichia coli - drug effects Escherichia coli - enzymology Escherichia coli - genetics Escherichia coli - growth & development Gene Dosage Genome, Bacterial Genomic Library Growth Inhibitors - administration & dosage Growth Inhibitors - chemistry Microbial Sensitivity Tests - statistics & numerical data Tetrahydrofolate Dehydrogenase - biosynthesis Tetrahydrofolate Dehydrogenase - physiology |
| title | Multicopy Suppressors for Novel Antibacterial Compounds Reveal Targets and Drug Efflux Susceptibility |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-11-28T23%3A30%3A25IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Multicopy%20Suppressors%20for%20Novel%20Antibacterial%20Compounds%20Reveal%20Targets%20and%20Drug%20Efflux%20Susceptibility&rft.jtitle=Chemistry%20&%20biology&rft.au=Li,%20Xiaoming&rft.date=2004-10-01&rft.volume=11&rft.issue=10&rft.spage=1423&rft.epage=1430&rft.pages=1423-1430&rft.issn=1074-5521&rft.eissn=1879-1301&rft_id=info:doi/10.1016/j.chembiol.2004.08.014&rft_dat=%3Cproquest_cross%3E66976618%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=19915232&rft_id=info:pmid/15489169&rft_els_id=S1074552104002492&rfr_iscdi=true |