Discovery and characterization of a novel class of pyrazolopyrimidinedione tRNA synthesis inhibitors

A high-throughput phenotypic screen for novel antibacterial agents led to the discovery of a novel pyrazolopyrimidinedione, PPD-1, with preferential activity against methicillin-resistant Staphylococcus aureus (MRSA). Resistance mapping revealed the likely target of inhibition to be lysyl tRNA synth...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of antibiotics 2015-06, Vol.68 (6), p.361-367
Hauptverfasser: Montgomery, Justin I, Smith, James F, Tomaras, Andrew P, Zaniewski, Richard, McPherson, Craig J, McAllister, Laura A, Hartman-Neumann, Sandra, Arcari, Joel T, Lescoe, Marykay, Gutierrez, Jemy, Yuan, Ying, Limberakis, Chris, Miller, Alita A
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 367
container_issue 6
container_start_page 361
container_title Journal of antibiotics
container_volume 68
creator Montgomery, Justin I
Smith, James F
Tomaras, Andrew P
Zaniewski, Richard
McPherson, Craig J
McAllister, Laura A
Hartman-Neumann, Sandra
Arcari, Joel T
Lescoe, Marykay
Gutierrez, Jemy
Yuan, Ying
Limberakis, Chris
Miller, Alita A
description A high-throughput phenotypic screen for novel antibacterial agents led to the discovery of a novel pyrazolopyrimidinedione, PPD-1, with preferential activity against methicillin-resistant Staphylococcus aureus (MRSA). Resistance mapping revealed the likely target of inhibition to be lysyl tRNA synthetase (LysRS). Preliminary structure–activity relationship (SAR) studies led to an analog, PPD-2, which gained Gram-negative antibacterial activity at the expense of MRSA activity and resistance to this compound mapped to prolyl tRNA synthetase (ProRS). These targets of inhibition were confirmed in vitro , with PPD-1 showing IC 50 s of 21.7 and 35 μ M in purified LysRS and ProRS enzyme assays, and PPD-2, 151 and 0.04 μ M , respectively. The highly attractive chemical properties of these compounds combined with intriguing preliminary SAR suggest that further exploration of this compelling novel series is warranted.
doi_str_mv 10.1038/ja.2014.163
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1692292842</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>4045462571</sourcerecordid><originalsourceid>FETCH-LOGICAL-c443t-303565c29979e7010d67295157df700e900e96a64d95460b14b7bc19dca73d5b3</originalsourceid><addsrcrecordid>eNp90UlLAzEUB_Agitbl5F0CXgSdmm2yHMUdREH0PGSS1KZMk5pMhfrpTamKiHgID5IfLy_5A7CP0RAjKk8nekgQZkPM6RoYYClxhRlX62CAEMGVlARtge2cJwhRQYXcBFukZpwpwQbAXvhs4ptLC6iDhWaskza9S_5d9z4GGEdQw1BAB02nc15uzBZJv8culuqn3vrgbKEO9o_3ZzAvQj922Wfow9i3vo8p74KNke6y2_usO-D56vLp_Ka6e7i-PT-7qwxjtK8oojWvDVFKKCcQRpYLompcCzsSCDm1XFxzZlWZH7WYtaI1WFmjBbV1S3fA0arvLMXXuct9My2vc12ng4vz3GCuCFFEMlLo4S86ifMUynQNoRRzIjiS_yksJJdSCqqKOl4pk2LOyY2aWfkYnRYNRs0yomaim2VEZQBa9MFnz3k7dfbbfmVSwMkK5HIUXlz6cekf_T4AqaKZVQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1786888739</pqid></control><display><type>article</type><title>Discovery and characterization of a novel class of pyrazolopyrimidinedione tRNA synthesis inhibitors</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Montgomery, Justin I ; Smith, James F ; Tomaras, Andrew P ; Zaniewski, Richard ; McPherson, Craig J ; McAllister, Laura A ; Hartman-Neumann, Sandra ; Arcari, Joel T ; Lescoe, Marykay ; Gutierrez, Jemy ; Yuan, Ying ; Limberakis, Chris ; Miller, Alita A</creator><creatorcontrib>Montgomery, Justin I ; Smith, James F ; Tomaras, Andrew P ; Zaniewski, Richard ; McPherson, Craig J ; McAllister, Laura A ; Hartman-Neumann, Sandra ; Arcari, Joel T ; Lescoe, Marykay ; Gutierrez, Jemy ; Yuan, Ying ; Limberakis, Chris ; Miller, Alita A</creatorcontrib><description>A high-throughput phenotypic screen for novel antibacterial agents led to the discovery of a novel pyrazolopyrimidinedione, PPD-1, with preferential activity against methicillin-resistant Staphylococcus aureus (MRSA). Resistance mapping revealed the likely target of inhibition to be lysyl tRNA synthetase (LysRS). Preliminary structure–activity relationship (SAR) studies led to an analog, PPD-2, which gained Gram-negative antibacterial activity at the expense of MRSA activity and resistance to this compound mapped to prolyl tRNA synthetase (ProRS). These targets of inhibition were confirmed in vitro , with PPD-1 showing IC 50 s of 21.7 and 35 μ M in purified LysRS and ProRS enzyme assays, and PPD-2, 151 and 0.04 μ M , respectively. The highly attractive chemical properties of these compounds combined with intriguing preliminary SAR suggest that further exploration of this compelling novel series is warranted.</description><identifier>ISSN: 0021-8820</identifier><identifier>EISSN: 1881-1469</identifier><identifier>DOI: 10.1038/ja.2014.163</identifier><identifier>PMID: 25464974</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject><![CDATA[631/92/609 ; Amino Acyl-tRNA Synthetases - antagonists & inhibitors ; Amino Acyl-tRNA Synthetases - genetics ; Amino Acyl-tRNA Synthetases - metabolism ; Anti-Bacterial Agents - chemical synthesis ; Anti-Bacterial Agents - chemistry ; Anti-Bacterial Agents - pharmacology ; Antibacterial agents ; Bacterial Proteins - antagonists & inhibitors ; Bacterial Proteins - genetics ; Bacterial Proteins - metabolism ; Bacteriology ; Biomedical and Life Sciences ; Bioorganic Chemistry ; Chemical properties ; Drug Design ; Drug Discovery ; Drug Resistance, Bacterial ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Escherichia coli - drug effects ; Escherichia coli - enzymology ; Escherichia coli - growth & development ; Escherichia coli Proteins - antagonists & inhibitors ; Escherichia coli Proteins - genetics ; Escherichia coli Proteins - metabolism ; High-Throughput Screening Assays ; Life Sciences ; Lysine-tRNA Ligase - antagonists & inhibitors ; Lysine-tRNA Ligase - genetics ; Lysine-tRNA Ligase - metabolism ; Medicinal Chemistry ; Methicillin Resistance ; Methicillin-Resistant Staphylococcus aureus - drug effects ; Methicillin-Resistant Staphylococcus aureus - enzymology ; Methicillin-Resistant Staphylococcus aureus - growth & development ; Microbial Sensitivity Tests ; Microbiology ; Neisseria gonorrhoeae - drug effects ; Neisseria gonorrhoeae - enzymology ; Neisseria gonorrhoeae - growth & development ; Organic Chemistry ; original-article ; Pseudomonas aeruginosa - drug effects ; Pseudomonas aeruginosa - enzymology ; Pseudomonas aeruginosa - growth & development ; Pyrazoles - chemical synthesis ; Pyrazoles - chemistry ; Pyrazoles - pharmacology ; Pyrimidinones - chemical synthesis ; Pyrimidinones - chemistry ; Pyrimidinones - pharmacology ; Recombinant Proteins - chemistry ; Recombinant Proteins - metabolism ; Staphylococcus infections ; Structure-Activity Relationship ; Transfer RNA Aminoacylation - drug effects]]></subject><ispartof>Journal of antibiotics, 2015-06, Vol.68 (6), p.361-367</ispartof><rights>Japan Antibiotics Research Association 2015</rights><rights>Copyright Nature Publishing Group Jun 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-303565c29979e7010d67295157df700e900e96a64d95460b14b7bc19dca73d5b3</citedby><cites>FETCH-LOGICAL-c443t-303565c29979e7010d67295157df700e900e96a64d95460b14b7bc19dca73d5b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25464974$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Montgomery, Justin I</creatorcontrib><creatorcontrib>Smith, James F</creatorcontrib><creatorcontrib>Tomaras, Andrew P</creatorcontrib><creatorcontrib>Zaniewski, Richard</creatorcontrib><creatorcontrib>McPherson, Craig J</creatorcontrib><creatorcontrib>McAllister, Laura A</creatorcontrib><creatorcontrib>Hartman-Neumann, Sandra</creatorcontrib><creatorcontrib>Arcari, Joel T</creatorcontrib><creatorcontrib>Lescoe, Marykay</creatorcontrib><creatorcontrib>Gutierrez, Jemy</creatorcontrib><creatorcontrib>Yuan, Ying</creatorcontrib><creatorcontrib>Limberakis, Chris</creatorcontrib><creatorcontrib>Miller, Alita A</creatorcontrib><title>Discovery and characterization of a novel class of pyrazolopyrimidinedione tRNA synthesis inhibitors</title><title>Journal of antibiotics</title><addtitle>J Antibiot</addtitle><addtitle>J Antibiot (Tokyo)</addtitle><description>A high-throughput phenotypic screen for novel antibacterial agents led to the discovery of a novel pyrazolopyrimidinedione, PPD-1, with preferential activity against methicillin-resistant Staphylococcus aureus (MRSA). Resistance mapping revealed the likely target of inhibition to be lysyl tRNA synthetase (LysRS). Preliminary structure–activity relationship (SAR) studies led to an analog, PPD-2, which gained Gram-negative antibacterial activity at the expense of MRSA activity and resistance to this compound mapped to prolyl tRNA synthetase (ProRS). These targets of inhibition were confirmed in vitro , with PPD-1 showing IC 50 s of 21.7 and 35 μ M in purified LysRS and ProRS enzyme assays, and PPD-2, 151 and 0.04 μ M , respectively. The highly attractive chemical properties of these compounds combined with intriguing preliminary SAR suggest that further exploration of this compelling novel series is warranted.</description><subject>631/92/609</subject><subject>Amino Acyl-tRNA Synthetases - antagonists &amp; inhibitors</subject><subject>Amino Acyl-tRNA Synthetases - genetics</subject><subject>Amino Acyl-tRNA Synthetases - metabolism</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>Bacterial Proteins - antagonists &amp; inhibitors</subject><subject>Bacterial Proteins - genetics</subject><subject>Bacterial Proteins - metabolism</subject><subject>Bacteriology</subject><subject>Biomedical and Life Sciences</subject><subject>Bioorganic Chemistry</subject><subject>Chemical properties</subject><subject>Drug Design</subject><subject>Drug Discovery</subject><subject>Drug Resistance, Bacterial</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Escherichia coli - drug effects</subject><subject>Escherichia coli - enzymology</subject><subject>Escherichia coli - growth &amp; development</subject><subject>Escherichia coli Proteins - antagonists &amp; inhibitors</subject><subject>Escherichia coli Proteins - genetics</subject><subject>Escherichia coli Proteins - metabolism</subject><subject>High-Throughput Screening Assays</subject><subject>Life Sciences</subject><subject>Lysine-tRNA Ligase - antagonists &amp; inhibitors</subject><subject>Lysine-tRNA Ligase - genetics</subject><subject>Lysine-tRNA Ligase - metabolism</subject><subject>Medicinal Chemistry</subject><subject>Methicillin Resistance</subject><subject>Methicillin-Resistant Staphylococcus aureus - drug effects</subject><subject>Methicillin-Resistant Staphylococcus aureus - enzymology</subject><subject>Methicillin-Resistant Staphylococcus aureus - growth &amp; development</subject><subject>Microbial Sensitivity Tests</subject><subject>Microbiology</subject><subject>Neisseria gonorrhoeae - drug effects</subject><subject>Neisseria gonorrhoeae - enzymology</subject><subject>Neisseria gonorrhoeae - growth &amp; development</subject><subject>Organic Chemistry</subject><subject>original-article</subject><subject>Pseudomonas aeruginosa - drug effects</subject><subject>Pseudomonas aeruginosa - enzymology</subject><subject>Pseudomonas aeruginosa - growth &amp; development</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - pharmacology</subject><subject>Pyrimidinones - chemical synthesis</subject><subject>Pyrimidinones - chemistry</subject><subject>Pyrimidinones - pharmacology</subject><subject>Recombinant Proteins - chemistry</subject><subject>Recombinant Proteins - metabolism</subject><subject>Staphylococcus infections</subject><subject>Structure-Activity Relationship</subject><subject>Transfer RNA Aminoacylation - drug effects</subject><issn>0021-8820</issn><issn>1881-1469</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp90UlLAzEUB_Agitbl5F0CXgSdmm2yHMUdREH0PGSS1KZMk5pMhfrpTamKiHgID5IfLy_5A7CP0RAjKk8nekgQZkPM6RoYYClxhRlX62CAEMGVlARtge2cJwhRQYXcBFukZpwpwQbAXvhs4ptLC6iDhWaskza9S_5d9z4GGEdQw1BAB02nc15uzBZJv8culuqn3vrgbKEO9o_3ZzAvQj922Wfow9i3vo8p74KNke6y2_usO-D56vLp_Ka6e7i-PT-7qwxjtK8oojWvDVFKKCcQRpYLompcCzsSCDm1XFxzZlWZH7WYtaI1WFmjBbV1S3fA0arvLMXXuct9My2vc12ng4vz3GCuCFFEMlLo4S86ifMUynQNoRRzIjiS_yksJJdSCqqKOl4pk2LOyY2aWfkYnRYNRs0yomaim2VEZQBa9MFnz3k7dfbbfmVSwMkK5HIUXlz6cekf_T4AqaKZVQ</recordid><startdate>20150601</startdate><enddate>20150601</enddate><creator>Montgomery, Justin I</creator><creator>Smith, James F</creator><creator>Tomaras, Andrew P</creator><creator>Zaniewski, Richard</creator><creator>McPherson, Craig J</creator><creator>McAllister, Laura A</creator><creator>Hartman-Neumann, Sandra</creator><creator>Arcari, Joel T</creator><creator>Lescoe, Marykay</creator><creator>Gutierrez, Jemy</creator><creator>Yuan, Ying</creator><creator>Limberakis, Chris</creator><creator>Miller, Alita A</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>3V.</scope><scope>7QL</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope></search><sort><creationdate>20150601</creationdate><title>Discovery and characterization of a novel class of pyrazolopyrimidinedione tRNA synthesis inhibitors</title><author>Montgomery, Justin I ; Smith, James F ; Tomaras, Andrew P ; Zaniewski, Richard ; McPherson, Craig J ; McAllister, Laura A ; Hartman-Neumann, Sandra ; Arcari, Joel T ; Lescoe, Marykay ; Gutierrez, Jemy ; Yuan, Ying ; Limberakis, Chris ; Miller, Alita A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c443t-303565c29979e7010d67295157df700e900e96a64d95460b14b7bc19dca73d5b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>631/92/609</topic><topic>Amino Acyl-tRNA Synthetases - antagonists &amp; inhibitors</topic><topic>Amino Acyl-tRNA Synthetases - genetics</topic><topic>Amino Acyl-tRNA Synthetases - metabolism</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>Bacterial Proteins - antagonists &amp; inhibitors</topic><topic>Bacterial Proteins - genetics</topic><topic>Bacterial Proteins - metabolism</topic><topic>Bacteriology</topic><topic>Biomedical and Life Sciences</topic><topic>Bioorganic Chemistry</topic><topic>Chemical properties</topic><topic>Drug Design</topic><topic>Drug Discovery</topic><topic>Drug Resistance, Bacterial</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Escherichia coli - drug effects</topic><topic>Escherichia coli - enzymology</topic><topic>Escherichia coli - growth &amp; development</topic><topic>Escherichia coli Proteins - antagonists &amp; inhibitors</topic><topic>Escherichia coli Proteins - genetics</topic><topic>Escherichia coli Proteins - metabolism</topic><topic>High-Throughput Screening Assays</topic><topic>Life Sciences</topic><topic>Lysine-tRNA Ligase - antagonists &amp; inhibitors</topic><topic>Lysine-tRNA Ligase - genetics</topic><topic>Lysine-tRNA Ligase - metabolism</topic><topic>Medicinal Chemistry</topic><topic>Methicillin Resistance</topic><topic>Methicillin-Resistant Staphylococcus aureus - drug effects</topic><topic>Methicillin-Resistant Staphylococcus aureus - enzymology</topic><topic>Methicillin-Resistant Staphylococcus aureus - growth &amp; development</topic><topic>Microbial Sensitivity Tests</topic><topic>Microbiology</topic><topic>Neisseria gonorrhoeae - drug effects</topic><topic>Neisseria gonorrhoeae - enzymology</topic><topic>Neisseria gonorrhoeae - growth &amp; development</topic><topic>Organic Chemistry</topic><topic>original-article</topic><topic>Pseudomonas aeruginosa - drug effects</topic><topic>Pseudomonas aeruginosa - enzymology</topic><topic>Pseudomonas aeruginosa - growth &amp; development</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - chemistry</topic><topic>Pyrazoles - pharmacology</topic><topic>Pyrimidinones - chemical synthesis</topic><topic>Pyrimidinones - chemistry</topic><topic>Pyrimidinones - pharmacology</topic><topic>Recombinant Proteins - chemistry</topic><topic>Recombinant Proteins - metabolism</topic><topic>Staphylococcus infections</topic><topic>Structure-Activity Relationship</topic><topic>Transfer RNA Aminoacylation - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Montgomery, Justin I</creatorcontrib><creatorcontrib>Smith, James F</creatorcontrib><creatorcontrib>Tomaras, Andrew P</creatorcontrib><creatorcontrib>Zaniewski, Richard</creatorcontrib><creatorcontrib>McPherson, Craig J</creatorcontrib><creatorcontrib>McAllister, Laura A</creatorcontrib><creatorcontrib>Hartman-Neumann, Sandra</creatorcontrib><creatorcontrib>Arcari, Joel T</creatorcontrib><creatorcontrib>Lescoe, Marykay</creatorcontrib><creatorcontrib>Gutierrez, Jemy</creatorcontrib><creatorcontrib>Yuan, Ying</creatorcontrib><creatorcontrib>Limberakis, Chris</creatorcontrib><creatorcontrib>Miller, Alita A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Immunology Abstracts</collection><collection>Health &amp; Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of antibiotics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Montgomery, Justin I</au><au>Smith, James F</au><au>Tomaras, Andrew P</au><au>Zaniewski, Richard</au><au>McPherson, Craig J</au><au>McAllister, Laura A</au><au>Hartman-Neumann, Sandra</au><au>Arcari, Joel T</au><au>Lescoe, Marykay</au><au>Gutierrez, Jemy</au><au>Yuan, Ying</au><au>Limberakis, Chris</au><au>Miller, Alita A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery and characterization of a novel class of pyrazolopyrimidinedione tRNA synthesis inhibitors</atitle><jtitle>Journal of antibiotics</jtitle><stitle>J Antibiot</stitle><addtitle>J Antibiot (Tokyo)</addtitle><date>2015-06-01</date><risdate>2015</risdate><volume>68</volume><issue>6</issue><spage>361</spage><epage>367</epage><pages>361-367</pages><issn>0021-8820</issn><eissn>1881-1469</eissn><abstract>A high-throughput phenotypic screen for novel antibacterial agents led to the discovery of a novel pyrazolopyrimidinedione, PPD-1, with preferential activity against methicillin-resistant Staphylococcus aureus (MRSA). Resistance mapping revealed the likely target of inhibition to be lysyl tRNA synthetase (LysRS). Preliminary structure–activity relationship (SAR) studies led to an analog, PPD-2, which gained Gram-negative antibacterial activity at the expense of MRSA activity and resistance to this compound mapped to prolyl tRNA synthetase (ProRS). These targets of inhibition were confirmed in vitro , with PPD-1 showing IC 50 s of 21.7 and 35 μ M in purified LysRS and ProRS enzyme assays, and PPD-2, 151 and 0.04 μ M , respectively. The highly attractive chemical properties of these compounds combined with intriguing preliminary SAR suggest that further exploration of this compelling novel series is warranted.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25464974</pmid><doi>10.1038/ja.2014.163</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 0021-8820
ispartof Journal of antibiotics, 2015-06, Vol.68 (6), p.361-367
issn 0021-8820
1881-1469
language eng
recordid cdi_proquest_miscellaneous_1692292842
source MEDLINE; EZB-FREE-00999 freely available EZB journals
subjects 631/92/609
Amino Acyl-tRNA Synthetases - antagonists & inhibitors
Amino Acyl-tRNA Synthetases - genetics
Amino Acyl-tRNA Synthetases - metabolism
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Antibacterial agents
Bacterial Proteins - antagonists & inhibitors
Bacterial Proteins - genetics
Bacterial Proteins - metabolism
Bacteriology
Biomedical and Life Sciences
Bioorganic Chemistry
Chemical properties
Drug Design
Drug Discovery
Drug Resistance, Bacterial
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Escherichia coli - drug effects
Escherichia coli - enzymology
Escherichia coli - growth & development
Escherichia coli Proteins - antagonists & inhibitors
Escherichia coli Proteins - genetics
Escherichia coli Proteins - metabolism
High-Throughput Screening Assays
Life Sciences
Lysine-tRNA Ligase - antagonists & inhibitors
Lysine-tRNA Ligase - genetics
Lysine-tRNA Ligase - metabolism
Medicinal Chemistry
Methicillin Resistance
Methicillin-Resistant Staphylococcus aureus - drug effects
Methicillin-Resistant Staphylococcus aureus - enzymology
Methicillin-Resistant Staphylococcus aureus - growth & development
Microbial Sensitivity Tests
Microbiology
Neisseria gonorrhoeae - drug effects
Neisseria gonorrhoeae - enzymology
Neisseria gonorrhoeae - growth & development
Organic Chemistry
original-article
Pseudomonas aeruginosa - drug effects
Pseudomonas aeruginosa - enzymology
Pseudomonas aeruginosa - growth & development
Pyrazoles - chemical synthesis
Pyrazoles - chemistry
Pyrazoles - pharmacology
Pyrimidinones - chemical synthesis
Pyrimidinones - chemistry
Pyrimidinones - pharmacology
Recombinant Proteins - chemistry
Recombinant Proteins - metabolism
Staphylococcus infections
Structure-Activity Relationship
Transfer RNA Aminoacylation - drug effects
title Discovery and characterization of a novel class of pyrazolopyrimidinedione tRNA synthesis inhibitors
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-28T01%3A21%3A10IST&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=Discovery%20and%20characterization%20of%20a%20novel%20class%20of%20pyrazolopyrimidinedione%20tRNA%20synthesis%20inhibitors&rft.jtitle=Journal%20of%20antibiotics&rft.au=Montgomery,%20Justin%20I&rft.date=2015-06-01&rft.volume=68&rft.issue=6&rft.spage=361&rft.epage=367&rft.pages=361-367&rft.issn=0021-8820&rft.eissn=1881-1469&rft_id=info:doi/10.1038/ja.2014.163&rft_dat=%3Cproquest_cross%3E4045462571%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=1786888739&rft_id=info:pmid/25464974&rfr_iscdi=true