Peptidomimetic Antibiotics Target Outer-Membrane Biogenesis in Pseudomonas aeruginosa
Antibiotics with new mechanisms of action are urgently required to combat the growing health threat posed by resistant pathogenic microorganisms. We synthesized a family of peptidomimetic antibiotics based on the antimicrobial peptide protegrin I. Several rounds of optimization gave a lead compound...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2010-02, Vol.327 (5968), p.1010-1013 |
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| creator | Srinivas, Nityakalyani Jetter, Peter Ueberbacher, Bernhard J Werneburg, Martina Zerbe, Katja Steinmann, Jessica Van der Meijden, Benjamin Bernardini, Francesca Lederer, Alexander Dias, Ricardo L.A Misson, Pauline E Henze, Heiko Zumbrunn, Jürg Gombert, Frank O Obrecht, Daniel Hunziker, Peter Schauer, Stefan Ziegler, Urs Käch, Andres Eberl, Leo Riedel, Kathrin DeMarco, Steven J Robinson, John A |
| description | Antibiotics with new mechanisms of action are urgently required to combat the growing health threat posed by resistant pathogenic microorganisms. We synthesized a family of peptidomimetic antibiotics based on the antimicrobial peptide protegrin I. Several rounds of optimization gave a lead compound that was active in the nanomolar range against Gram-negative Pseudomonas spp., but was largely inactive against other Gram-negative and Gram-positive bacteria. Biochemical and genetic studies showed that the peptidomimetics had a non-membrane-lytic mechanism of action and identified a homolog of the β-barrel protein LptD (Imp/OstA), which functions in outer-membrane biogenesis, as a cellular target. The peptidomimetic showed potent antimicrobial activity in a mouse septicemia infection model. Drug-resistant strains of Pseudomonas are a serious health problem, so this family of antibiotics may have important therapeutic applications. |
| doi_str_mv | 10.1126/science.1182749 |
| format | Article |
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We synthesized a family of peptidomimetic antibiotics based on the antimicrobial peptide protegrin I. Several rounds of optimization gave a lead compound that was active in the nanomolar range against Gram-negative Pseudomonas spp., but was largely inactive against other Gram-negative and Gram-positive bacteria. Biochemical and genetic studies showed that the peptidomimetics had a non-membrane-lytic mechanism of action and identified a homolog of the β-barrel protein LptD (Imp/OstA), which functions in outer-membrane biogenesis, as a cellular target. The peptidomimetic showed potent antimicrobial activity in a mouse septicemia infection model. Drug-resistant strains of Pseudomonas are a serious health problem, so this family of antibiotics may have important therapeutic applications.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.1182749</identifier><identifier>PMID: 20167788</identifier><identifier>CODEN: SCIEAS</identifier><language>eng</language><publisher>Washington, DC: American Association for the Advancement of Science</publisher><subject>Animals ; Anti-Bacterial Agents - chemical synthesis ; Anti-Bacterial Agents - metabolism ; Anti-Bacterial Agents - pharmacology ; Antibacterial agents ; Antibiotics ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antimicrobial Cationic Peptides - chemistry ; Antimicrobials ; Bacteria ; Bacterial Outer Membrane Proteins - chemistry ; Bacterial Outer Membrane Proteins - genetics ; Bacterial Outer Membrane Proteins - metabolism ; Biological and medical sciences ; Cell growth ; Cell Membrane - metabolism ; Cell membranes ; DNA ; Drug Design ; Drug resistance ; Drug Resistance, Bacterial - genetics ; Fluorescence ; Genes, Bacterial ; Libraries ; Lipids ; Lipopolysaccharides - metabolism ; Medical sciences ; Membranes ; Mice ; Microbial Sensitivity Tests ; Molecular Mimicry ; Mutation ; Peptide Library ; Peptides - chemical synthesis ; Peptides - chemistry ; Peptides - metabolism ; Peptides - pharmacology ; Peptidomimetics ; Pharmacology ; Pharmacology. Drug treatments ; Protein Structure, Tertiary ; Proteins ; Pseudomonas aeruginosa ; Pseudomonas aeruginosa - drug effects ; Pseudomonas aeruginosa - growth & development ; Pseudomonas aeruginosa - metabolism ; Pseudomonas aeruginosa - ultrastructure ; Pseudomonas Infections - drug therapy ; Pseudomonas Infections - microbiology ; Sepsis - drug therapy ; Sepsis - microbiology</subject><ispartof>Science (American Association for the Advancement of Science), 2010-02, Vol.327 (5968), p.1010-1013</ispartof><rights>Copyright 2009 American Association for the Advancement of Science</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2010, American Association for the Advancement of Science</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c534t-35904f3a8cb156951b65f147c15a5e4b0b280794ac2d40da1640e2620717cc3a3</citedby><cites>FETCH-LOGICAL-c534t-35904f3a8cb156951b65f147c15a5e4b0b280794ac2d40da1640e2620717cc3a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/40509965$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/40509965$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>314,776,780,799,2871,2872,27901,27902,57992,58225</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22453813$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20167788$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Srinivas, Nityakalyani</creatorcontrib><creatorcontrib>Jetter, Peter</creatorcontrib><creatorcontrib>Ueberbacher, Bernhard J</creatorcontrib><creatorcontrib>Werneburg, Martina</creatorcontrib><creatorcontrib>Zerbe, Katja</creatorcontrib><creatorcontrib>Steinmann, Jessica</creatorcontrib><creatorcontrib>Van der Meijden, Benjamin</creatorcontrib><creatorcontrib>Bernardini, Francesca</creatorcontrib><creatorcontrib>Lederer, Alexander</creatorcontrib><creatorcontrib>Dias, Ricardo L.A</creatorcontrib><creatorcontrib>Misson, Pauline E</creatorcontrib><creatorcontrib>Henze, Heiko</creatorcontrib><creatorcontrib>Zumbrunn, Jürg</creatorcontrib><creatorcontrib>Gombert, Frank O</creatorcontrib><creatorcontrib>Obrecht, Daniel</creatorcontrib><creatorcontrib>Hunziker, Peter</creatorcontrib><creatorcontrib>Schauer, Stefan</creatorcontrib><creatorcontrib>Ziegler, Urs</creatorcontrib><creatorcontrib>Käch, Andres</creatorcontrib><creatorcontrib>Eberl, Leo</creatorcontrib><creatorcontrib>Riedel, Kathrin</creatorcontrib><creatorcontrib>DeMarco, Steven J</creatorcontrib><creatorcontrib>Robinson, John A</creatorcontrib><title>Peptidomimetic Antibiotics Target Outer-Membrane Biogenesis in Pseudomonas aeruginosa</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Antibiotics with new mechanisms of action are urgently required to combat the growing health threat posed by resistant pathogenic microorganisms. We synthesized a family of peptidomimetic antibiotics based on the antimicrobial peptide protegrin I. Several rounds of optimization gave a lead compound that was active in the nanomolar range against Gram-negative Pseudomonas spp., but was largely inactive against other Gram-negative and Gram-positive bacteria. Biochemical and genetic studies showed that the peptidomimetics had a non-membrane-lytic mechanism of action and identified a homolog of the β-barrel protein LptD (Imp/OstA), which functions in outer-membrane biogenesis, as a cellular target. The peptidomimetic showed potent antimicrobial activity in a mouse septicemia infection model. Drug-resistant strains of Pseudomonas are a serious health problem, so this family of antibiotics may have important therapeutic applications.</description><subject>Animals</subject><subject>Anti-Bacterial Agents - chemical synthesis</subject><subject>Anti-Bacterial Agents - metabolism</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Antibacterial agents</subject><subject>Antibiotics</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antimicrobial Cationic Peptides - chemistry</subject><subject>Antimicrobials</subject><subject>Bacteria</subject><subject>Bacterial Outer Membrane Proteins - chemistry</subject><subject>Bacterial Outer Membrane Proteins - genetics</subject><subject>Bacterial Outer Membrane Proteins - metabolism</subject><subject>Biological and medical sciences</subject><subject>Cell growth</subject><subject>Cell Membrane - metabolism</subject><subject>Cell membranes</subject><subject>DNA</subject><subject>Drug Design</subject><subject>Drug resistance</subject><subject>Drug Resistance, Bacterial - genetics</subject><subject>Fluorescence</subject><subject>Genes, Bacterial</subject><subject>Libraries</subject><subject>Lipids</subject><subject>Lipopolysaccharides - metabolism</subject><subject>Medical sciences</subject><subject>Membranes</subject><subject>Mice</subject><subject>Microbial Sensitivity Tests</subject><subject>Molecular Mimicry</subject><subject>Mutation</subject><subject>Peptide Library</subject><subject>Peptides - chemical synthesis</subject><subject>Peptides - chemistry</subject><subject>Peptides - metabolism</subject><subject>Peptides - pharmacology</subject><subject>Peptidomimetics</subject><subject>Pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins</subject><subject>Pseudomonas aeruginosa</subject><subject>Pseudomonas aeruginosa - drug effects</subject><subject>Pseudomonas aeruginosa - growth & development</subject><subject>Pseudomonas aeruginosa - metabolism</subject><subject>Pseudomonas aeruginosa - ultrastructure</subject><subject>Pseudomonas Infections - drug therapy</subject><subject>Pseudomonas Infections - microbiology</subject><subject>Sepsis - drug therapy</subject><subject>Sepsis - microbiology</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0UFvFCEUB3BiNHatnj2pE5PqaeyDBwwca2PVpKZN7J4nDMts2OwMW5g5-O19ZseaeNATkPfj8cifsZccPnAu9HnxMYw-0MGIRtpHbMXBqtoKwMdsBYC6NtCoE_aslB0A1Sw-ZScCuG4aY1ZsfRsOU9ykIQ5hir66GKfYxUTbUt25vA1TdTNPIdffwtBlN4bqY0zbMIYSSxXH6raEmW6n0ZXKhTxv45iKe86e9G5fwotlPWXrq093l1_q65vPXy8vrmuvUE41KguyR2d8x5W2inda9Vw2niunguygEzS9lc6LjYSN41pCEFpAwxvv0eEpe3_se8jpfg5laodYfNjvadA0l7aRiJaDhP9LRCEsR0ny3T-l4BK5QE3w7V9wl-Y80n_J0NeMEYLQ-RH5nErJoW8POQ4u_2g5tL8ibJcI2yVCuvF6aTt3Q9g8-N-ZEThbgCve7XtKxcfyxwmp0HAk9-rodmVK-aEuQYG1WlH9zbHeu9S6baYe6-_0CgI3oLTU-BMVF7aX</recordid><startdate>20100219</startdate><enddate>20100219</enddate><creator>Srinivas, Nityakalyani</creator><creator>Jetter, Peter</creator><creator>Ueberbacher, Bernhard J</creator><creator>Werneburg, Martina</creator><creator>Zerbe, Katja</creator><creator>Steinmann, Jessica</creator><creator>Van der Meijden, Benjamin</creator><creator>Bernardini, Francesca</creator><creator>Lederer, Alexander</creator><creator>Dias, Ricardo L.A</creator><creator>Misson, Pauline E</creator><creator>Henze, Heiko</creator><creator>Zumbrunn, Jürg</creator><creator>Gombert, Frank O</creator><creator>Obrecht, Daniel</creator><creator>Hunziker, Peter</creator><creator>Schauer, Stefan</creator><creator>Ziegler, Urs</creator><creator>Käch, Andres</creator><creator>Eberl, Leo</creator><creator>Riedel, Kathrin</creator><creator>DeMarco, Steven J</creator><creator>Robinson, John A</creator><general>American Association for the Advancement of Science</general><general>The American Association for the Advancement of Science</general><scope>FBQ</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>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20100219</creationdate><title>Peptidomimetic Antibiotics Target Outer-Membrane Biogenesis in Pseudomonas aeruginosa</title><author>Srinivas, Nityakalyani ; Jetter, Peter ; Ueberbacher, Bernhard J ; Werneburg, Martina ; Zerbe, Katja ; Steinmann, Jessica ; Van der Meijden, Benjamin ; Bernardini, Francesca ; Lederer, Alexander ; Dias, Ricardo L.A ; Misson, Pauline E ; Henze, Heiko ; Zumbrunn, Jürg ; Gombert, Frank O ; Obrecht, Daniel ; Hunziker, Peter ; Schauer, Stefan ; Ziegler, Urs ; Käch, Andres ; Eberl, Leo ; Riedel, Kathrin ; DeMarco, Steven J ; Robinson, John A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c534t-35904f3a8cb156951b65f147c15a5e4b0b280794ac2d40da1640e2620717cc3a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Anti-Bacterial Agents - chemical synthesis</topic><topic>Anti-Bacterial Agents - metabolism</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Antibacterial agents</topic><topic>Antibiotics</topic><topic>Antibiotics. 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Antiparasitic agents</topic><topic>Antimicrobial Cationic Peptides - chemistry</topic><topic>Antimicrobials</topic><topic>Bacteria</topic><topic>Bacterial Outer Membrane Proteins - chemistry</topic><topic>Bacterial Outer Membrane Proteins - genetics</topic><topic>Bacterial Outer Membrane Proteins - metabolism</topic><topic>Biological and medical sciences</topic><topic>Cell growth</topic><topic>Cell Membrane - metabolism</topic><topic>Cell membranes</topic><topic>DNA</topic><topic>Drug Design</topic><topic>Drug resistance</topic><topic>Drug Resistance, Bacterial - genetics</topic><topic>Fluorescence</topic><topic>Genes, Bacterial</topic><topic>Libraries</topic><topic>Lipids</topic><topic>Lipopolysaccharides - metabolism</topic><topic>Medical sciences</topic><topic>Membranes</topic><topic>Mice</topic><topic>Microbial Sensitivity Tests</topic><topic>Molecular Mimicry</topic><topic>Mutation</topic><topic>Peptide Library</topic><topic>Peptides - chemical synthesis</topic><topic>Peptides - chemistry</topic><topic>Peptides - metabolism</topic><topic>Peptides - pharmacology</topic><topic>Peptidomimetics</topic><topic>Pharmacology</topic><topic>Pharmacology. 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We synthesized a family of peptidomimetic antibiotics based on the antimicrobial peptide protegrin I. Several rounds of optimization gave a lead compound that was active in the nanomolar range against Gram-negative Pseudomonas spp., but was largely inactive against other Gram-negative and Gram-positive bacteria. Biochemical and genetic studies showed that the peptidomimetics had a non-membrane-lytic mechanism of action and identified a homolog of the β-barrel protein LptD (Imp/OstA), which functions in outer-membrane biogenesis, as a cellular target. The peptidomimetic showed potent antimicrobial activity in a mouse septicemia infection model. 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| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2010-02, Vol.327 (5968), p.1010-1013 |
| issn | 0036-8075 1095-9203 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_743391040 |
| source | Jstor Complete Legacy; MEDLINE; Science Magazine |
| subjects | Animals Anti-Bacterial Agents - chemical synthesis Anti-Bacterial Agents - metabolism Anti-Bacterial Agents - pharmacology Antibacterial agents Antibiotics Antibiotics. Antiinfectious agents. Antiparasitic agents Antimicrobial Cationic Peptides - chemistry Antimicrobials Bacteria Bacterial Outer Membrane Proteins - chemistry Bacterial Outer Membrane Proteins - genetics Bacterial Outer Membrane Proteins - metabolism Biological and medical sciences Cell growth Cell Membrane - metabolism Cell membranes DNA Drug Design Drug resistance Drug Resistance, Bacterial - genetics Fluorescence Genes, Bacterial Libraries Lipids Lipopolysaccharides - metabolism Medical sciences Membranes Mice Microbial Sensitivity Tests Molecular Mimicry Mutation Peptide Library Peptides - chemical synthesis Peptides - chemistry Peptides - metabolism Peptides - pharmacology Peptidomimetics Pharmacology Pharmacology. Drug treatments Protein Structure, Tertiary Proteins Pseudomonas aeruginosa Pseudomonas aeruginosa - drug effects Pseudomonas aeruginosa - growth & development Pseudomonas aeruginosa - metabolism Pseudomonas aeruginosa - ultrastructure Pseudomonas Infections - drug therapy Pseudomonas Infections - microbiology Sepsis - drug therapy Sepsis - microbiology |
| title | Peptidomimetic Antibiotics Target Outer-Membrane Biogenesis in Pseudomonas aeruginosa |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T20%3A53%3A49IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Peptidomimetic%20Antibiotics%20Target%20Outer-Membrane%20Biogenesis%20in%20Pseudomonas%20aeruginosa&rft.jtitle=Science%20(American%20Association%20for%20the%20Advancement%20of%20Science)&rft.au=Srinivas,%20Nityakalyani&rft.date=2010-02-19&rft.volume=327&rft.issue=5968&rft.spage=1010&rft.epage=1013&rft.pages=1010-1013&rft.issn=0036-8075&rft.eissn=1095-9203&rft.coden=SCIEAS&rft_id=info:doi/10.1126/science.1182749&rft_dat=%3Cjstor_proqu%3E40509965%3C/jstor_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=213598822&rft_id=info:pmid/20167788&rft_jstor_id=40509965&rfr_iscdi=true |