GLYCOPEPTIDE ANTIBIOTICS: A MECHANISM-BASED SCREEN EMPLOYING A BACTERIAL CELL WALL RECEPTOR MIMETIC
The evolution of a highly targeted screening program for the discovery of antibiotics of the glycopeptide (vancomycin) class is described. A holistic approach was utilized which optimized not just screening techniques but also the selection of candidate producer cultures and their growth under condi...
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| Veröffentlicht in: | Journal of antibiotics 1986, Vol.39(1), pp.58-67 |
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| container_start_page | 58 |
| container_title | Journal of antibiotics |
| container_volume | 39 |
| creator | RAKE, J. B. GERBER, R. MEHTA, R. J. NEWMAN, D. J. OH, Y. K. PHELEN, C. SHEARER, M. C. SITRIN, R. D. NISBET, L. J. |
| description | The evolution of a highly targeted screening program for the discovery of antibiotics of the glycopeptide (vancomycin) class is described. A holistic approach was utilized which optimized not just screening techniques but also the selection of candidate producer cultures and their growth under conditions which enhanced production of target compounds. Two screen techniques were utilized; differential inhibition of a vancomycin-resistant strain and its susceptible parent, and a specific antagonism screen using the reversal of glycopeptide activity by a tripeptide analog of the glycopeptide receptor, diacetyl-L-lysyl-D-alanyl-D-alanine. The latter screen was 2- to 32-fold more sensitive to known glycopeptides than the former, and was absolutely specific, yielding no false positive responses. The use of the tripeptide antagonism assay, combined with optimized culture selection and growth conditions yielded novel glycopeptide antibiotics at a rate of 1 per 320 cultures screened. With a holistic approach to screening and properly optimized techniques, large numbers of cultures do not need to be examined in order to discover novel antibiotics. |
| doi_str_mv | 10.7164/antibiotics.39.58 |
| format | Article |
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B. ; GERBER, R. ; MEHTA, R. J. ; NEWMAN, D. J. ; OH, Y. K. ; PHELEN, C. ; SHEARER, M. C. ; SITRIN, R. D. ; NISBET, L. J.</creator><creatorcontrib>RAKE, J. B. ; GERBER, R. ; MEHTA, R. J. ; NEWMAN, D. J. ; OH, Y. K. ; PHELEN, C. ; SHEARER, M. C. ; SITRIN, R. D. ; NISBET, L. J.</creatorcontrib><description>The evolution of a highly targeted screening program for the discovery of antibiotics of the glycopeptide (vancomycin) class is described. A holistic approach was utilized which optimized not just screening techniques but also the selection of candidate producer cultures and their growth under conditions which enhanced production of target compounds. Two screen techniques were utilized; differential inhibition of a vancomycin-resistant strain and its susceptible parent, and a specific antagonism screen using the reversal of glycopeptide activity by a tripeptide analog of the glycopeptide receptor, diacetyl-L-lysyl-D-alanyl-D-alanine. The latter screen was 2- to 32-fold more sensitive to known glycopeptides than the former, and was absolutely specific, yielding no false positive responses. The use of the tripeptide antagonism assay, combined with optimized culture selection and growth conditions yielded novel glycopeptide antibiotics at a rate of 1 per 320 cultures screened. With a holistic approach to screening and properly optimized techniques, large numbers of cultures do not need to be examined in order to discover novel antibiotics.</description><identifier>ISSN: 0021-8820</identifier><identifier>EISSN: 1881-1469</identifier><identifier>DOI: 10.7164/antibiotics.39.58</identifier><identifier>PMID: 3949630</identifier><identifier>CODEN: JANTAJ</identifier><language>eng</language><publisher>Tokyo: JAPAN ANTIBIOTICS RESEARCH ASSOCIATION</publisher><subject>Actinomycetales - analysis ; Anti-Bacterial Agents - pharmacology ; Antibiotics (antibacterial agents, antifungal agents) ; Antibiotics, microbial producers, chemotherapic agents, antiseptics, disinfecting agents ; Applied microbiology ; Biological and medical sciences ; Cell Wall - drug effects ; Drug Resistance, Microbial ; False Positive Reactions ; Fundamental and applied biological sciences. Psychology ; Glycopeptides - pharmacology ; Methods ; Microbial Sensitivity Tests ; Microbiology ; Vancomycin - pharmacology</subject><ispartof>The Journal of Antibiotics, 1986, Vol.39(1), pp.58-67</ispartof><rights>Japan Antibiotics Research Association</rights><rights>1986 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c638t-ecaff84bf9abfcf7e3ab9af161b9a0fc2a22c91c98b8ef7baf1f73910565fc3f3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,1876,4009,27902,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=8617435$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/3949630$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>RAKE, J. B.</creatorcontrib><creatorcontrib>GERBER, R.</creatorcontrib><creatorcontrib>MEHTA, R. J.</creatorcontrib><creatorcontrib>NEWMAN, D. J.</creatorcontrib><creatorcontrib>OH, Y. K.</creatorcontrib><creatorcontrib>PHELEN, C.</creatorcontrib><creatorcontrib>SHEARER, M. C.</creatorcontrib><creatorcontrib>SITRIN, R. D.</creatorcontrib><creatorcontrib>NISBET, L. J.</creatorcontrib><title>GLYCOPEPTIDE ANTIBIOTICS: A MECHANISM-BASED SCREEN EMPLOYING A BACTERIAL CELL WALL RECEPTOR MIMETIC</title><title>Journal of antibiotics</title><addtitle>J. Antibiot.</addtitle><description>The evolution of a highly targeted screening program for the discovery of antibiotics of the glycopeptide (vancomycin) class is described. A holistic approach was utilized which optimized not just screening techniques but also the selection of candidate producer cultures and their growth under conditions which enhanced production of target compounds. Two screen techniques were utilized; differential inhibition of a vancomycin-resistant strain and its susceptible parent, and a specific antagonism screen using the reversal of glycopeptide activity by a tripeptide analog of the glycopeptide receptor, diacetyl-L-lysyl-D-alanyl-D-alanine. The latter screen was 2- to 32-fold more sensitive to known glycopeptides than the former, and was absolutely specific, yielding no false positive responses. The use of the tripeptide antagonism assay, combined with optimized culture selection and growth conditions yielded novel glycopeptide antibiotics at a rate of 1 per 320 cultures screened. With a holistic approach to screening and properly optimized techniques, large numbers of cultures do not need to be examined in order to discover novel antibiotics.</description><subject>Actinomycetales - analysis</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Antibiotics (antibacterial agents, antifungal agents)</subject><subject>Antibiotics, microbial producers, chemotherapic agents, antiseptics, disinfecting agents</subject><subject>Applied microbiology</subject><subject>Biological and medical sciences</subject><subject>Cell Wall - drug effects</subject><subject>Drug Resistance, Microbial</subject><subject>False Positive Reactions</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Glycopeptides - pharmacology</subject><subject>Methods</subject><subject>Microbial Sensitivity Tests</subject><subject>Microbiology</subject><subject>Vancomycin - pharmacology</subject><issn>0021-8820</issn><issn>1881-1469</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1986</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkE2P0zAYhC0EWsrCD-CAlAPaW4odJ_7glnpN1yhpqjYI7clyjA1Zpe0Spwf-Pa5aVXt538M8MyMNAB8RnFNE8i9mP_Vdf5h6G-aYzwv2CswQYyhFOeGvwQzCDKWMZfAteBfCE4SYYspuwA3mOScYzoBdVo-iWct1q-5lUq5atVBNq8T2a1ImtRQP5Upt63RRbuV9shUbKVeJrNdV86hWy4gsStHKjSqrRMiqSn6W8WykiHnNJqlVLWPWe_DGmyG4D5d_C358k614SKtmqURZpZZgNqXOGu9Z3nluOm89ddh03HhEUHzQ28xkmeXIctYx52kXJU8xR7AghbfY41twd859Hg9_jy5MetcH64bB7N3hGDQlNMOUFhFEZ9COhxBG5_Xz2O_M-E8jqE_D6hfDasx1waLn0yX82O3cr6vjsmTUP190E6wZ_Gj2tg9XjBFEc3yq_n7GnsJkfrurbsbYNbiXxYgTdipH51OwK2T_mFG7Pf4PSCKYDw</recordid><startdate>1986</startdate><enddate>1986</enddate><creator>RAKE, J. B.</creator><creator>GERBER, R.</creator><creator>MEHTA, R. J.</creator><creator>NEWMAN, D. J.</creator><creator>OH, Y. K.</creator><creator>PHELEN, C.</creator><creator>SHEARER, M. C.</creator><creator>SITRIN, R. D.</creator><creator>NISBET, L. J.</creator><general>JAPAN ANTIBIOTICS RESEARCH ASSOCIATION</general><general>Japan Antibiotics Research Association</general><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>7X8</scope></search><sort><creationdate>1986</creationdate><title>GLYCOPEPTIDE ANTIBIOTICS: A MECHANISM-BASED SCREEN EMPLOYING A BACTERIAL CELL WALL RECEPTOR MIMETIC</title><author>RAKE, J. B. ; GERBER, R. ; MEHTA, R. J. ; NEWMAN, D. J. ; OH, Y. K. ; PHELEN, C. ; SHEARER, M. C. ; SITRIN, R. D. ; NISBET, L. 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Psychology</topic><topic>Glycopeptides - pharmacology</topic><topic>Methods</topic><topic>Microbial Sensitivity Tests</topic><topic>Microbiology</topic><topic>Vancomycin - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>RAKE, J. B.</creatorcontrib><creatorcontrib>GERBER, R.</creatorcontrib><creatorcontrib>MEHTA, R. J.</creatorcontrib><creatorcontrib>NEWMAN, D. J.</creatorcontrib><creatorcontrib>OH, Y. K.</creatorcontrib><creatorcontrib>PHELEN, C.</creatorcontrib><creatorcontrib>SHEARER, M. C.</creatorcontrib><creatorcontrib>SITRIN, R. D.</creatorcontrib><creatorcontrib>NISBET, L. 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Antibiot.</addtitle><date>1986</date><risdate>1986</risdate><volume>39</volume><issue>1</issue><spage>58</spage><epage>67</epage><pages>58-67</pages><issn>0021-8820</issn><eissn>1881-1469</eissn><coden>JANTAJ</coden><abstract>The evolution of a highly targeted screening program for the discovery of antibiotics of the glycopeptide (vancomycin) class is described. A holistic approach was utilized which optimized not just screening techniques but also the selection of candidate producer cultures and their growth under conditions which enhanced production of target compounds. Two screen techniques were utilized; differential inhibition of a vancomycin-resistant strain and its susceptible parent, and a specific antagonism screen using the reversal of glycopeptide activity by a tripeptide analog of the glycopeptide receptor, diacetyl-L-lysyl-D-alanyl-D-alanine. The latter screen was 2- to 32-fold more sensitive to known glycopeptides than the former, and was absolutely specific, yielding no false positive responses. The use of the tripeptide antagonism assay, combined with optimized culture selection and growth conditions yielded novel glycopeptide antibiotics at a rate of 1 per 320 cultures screened. With a holistic approach to screening and properly optimized techniques, large numbers of cultures do not need to be examined in order to discover novel antibiotics.</abstract><cop>Tokyo</cop><pub>JAPAN ANTIBIOTICS RESEARCH ASSOCIATION</pub><pmid>3949630</pmid><doi>10.7164/antibiotics.39.58</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0021-8820 |
| ispartof | The Journal of Antibiotics, 1986, Vol.39(1), pp.58-67 |
| issn | 0021-8820 1881-1469 |
| language | eng |
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| source | J-STAGE Free; MEDLINE |
| subjects | Actinomycetales - analysis Anti-Bacterial Agents - pharmacology Antibiotics (antibacterial agents, antifungal agents) Antibiotics, microbial producers, chemotherapic agents, antiseptics, disinfecting agents Applied microbiology Biological and medical sciences Cell Wall - drug effects Drug Resistance, Microbial False Positive Reactions Fundamental and applied biological sciences. Psychology Glycopeptides - pharmacology Methods Microbial Sensitivity Tests Microbiology Vancomycin - pharmacology |
| title | GLYCOPEPTIDE ANTIBIOTICS: A MECHANISM-BASED SCREEN EMPLOYING A BACTERIAL CELL WALL RECEPTOR MIMETIC |
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