Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase‑1
The efficacy of β-lactam antibiotics is threatened by the emergence and global spread of metallo-β-lactamase (MBL) mediated resistance, specifically New Delhi metallo-β-lactamase-1 (NDM-1). By utilization of fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related β-...
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| Veröffentlicht in: | Journal of medicinal chemistry 2017-09, Vol.60 (17), p.7267-7283 |
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| creator | Chen, Allie Y Thomas, Pei W Stewart, Alesha C Bergstrom, Alexander Cheng, Zishuo Miller, Callie Bethel, Christopher R Marshall, Steven H Credille, Cy V Riley, Christopher L Page, Richard C Bonomo, Robert A Crowder, Michael W Tierney, David L Fast, Walter Cohen, Seth M |
| description | The efficacy of β-lactam antibiotics is threatened by the emergence and global spread of metallo-β-lactamase (MBL) mediated resistance, specifically New Delhi metallo-β-lactamase-1 (NDM-1). By utilization of fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related β-lactamases, IMP-1 and VIM-2, was identified. On the basis of 2,6-dipicolinic acid (DPA), several libraries were synthesized for structure–activity relationship (SAR) analysis. Inhibitor 36 (IC50 = 80 nM) was identified to be highly selective for MBLs when compared to other Zn(II) metalloenzymes. While DPA displayed a propensity to chelate metal ions from NDM-1, 36 formed a stable NDM-1:Zn(II):inhibitor ternary complex, as demonstrated by 1H NMR, electron paramagnetic resonance (EPR) spectroscopy, equilibrium dialysis, intrinsic tryptophan fluorescence emission, and UV–vis spectroscopy. When coadministered with 36 (at concentrations nontoxic to mammalian cells), the minimum inhibitory concentrations (MICs) of imipenem against clinical isolates of Eschericia coli and Klebsiella pneumoniae harboring NDM-1 were reduced to susceptible levels. |
| doi_str_mv | 10.1021/acs.jmedchem.7b00407 |
| format | Article |
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By utilization of fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related β-lactamases, IMP-1 and VIM-2, was identified. On the basis of 2,6-dipicolinic acid (DPA), several libraries were synthesized for structure–activity relationship (SAR) analysis. Inhibitor 36 (IC50 = 80 nM) was identified to be highly selective for MBLs when compared to other Zn(II) metalloenzymes. While DPA displayed a propensity to chelate metal ions from NDM-1, 36 formed a stable NDM-1:Zn(II):inhibitor ternary complex, as demonstrated by 1H NMR, electron paramagnetic resonance (EPR) spectroscopy, equilibrium dialysis, intrinsic tryptophan fluorescence emission, and UV–vis spectroscopy. When coadministered with 36 (at concentrations nontoxic to mammalian cells), the minimum inhibitory concentrations (MICs) of imipenem against clinical isolates of Eschericia coli and Klebsiella pneumoniae harboring NDM-1 were reduced to susceptible levels.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.7b00407</identifier><identifier>PMID: 28809565</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Anti-Bacterial Agents - chemistry ; Anti-Bacterial Agents - pharmacology ; beta-Lactamase Inhibitors - chemistry ; beta-Lactamase Inhibitors - pharmacology ; beta-Lactamases - metabolism ; Escherichia coli - drug effects ; Escherichia coli - enzymology ; Escherichia coli Infections - drug therapy ; Escherichia coli Infections - microbiology ; Humans ; Klebsiella Infections - drug therapy ; Klebsiella Infections - microbiology ; Klebsiella pneumoniae - drug effects ; Klebsiella pneumoniae - enzymology ; Microbial Sensitivity Tests ; Picolinic Acids - chemistry ; Picolinic Acids - pharmacology ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2017-09, Vol.60 (17), p.7267-7283</ispartof><rights>Copyright © 2017 American Chemical Society</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a449t-1e25bdf4615258734381b90ffc725810f4acedacdcfab0066e58642caa19f4d43</citedby><cites>FETCH-LOGICAL-a449t-1e25bdf4615258734381b90ffc725810f4acedacdcfab0066e58642caa19f4d43</cites><orcidid>0000-0002-5597-799X ; 0000-0002-3138-0283 ; 0000-0001-7567-2213 ; 0000-0002-5233-2280 ; 0000-0002-3006-3171 ; 0000-0002-3299-894X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.7b00407$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.7b00407$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28809565$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Allie Y</creatorcontrib><creatorcontrib>Thomas, Pei W</creatorcontrib><creatorcontrib>Stewart, Alesha C</creatorcontrib><creatorcontrib>Bergstrom, Alexander</creatorcontrib><creatorcontrib>Cheng, Zishuo</creatorcontrib><creatorcontrib>Miller, Callie</creatorcontrib><creatorcontrib>Bethel, Christopher R</creatorcontrib><creatorcontrib>Marshall, Steven H</creatorcontrib><creatorcontrib>Credille, Cy V</creatorcontrib><creatorcontrib>Riley, Christopher L</creatorcontrib><creatorcontrib>Page, Richard C</creatorcontrib><creatorcontrib>Bonomo, Robert A</creatorcontrib><creatorcontrib>Crowder, Michael W</creatorcontrib><creatorcontrib>Tierney, David L</creatorcontrib><creatorcontrib>Fast, Walter</creatorcontrib><creatorcontrib>Cohen, Seth M</creatorcontrib><title>Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase‑1</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The efficacy of β-lactam antibiotics is threatened by the emergence and global spread of metallo-β-lactamase (MBL) mediated resistance, specifically New Delhi metallo-β-lactamase-1 (NDM-1). By utilization of fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related β-lactamases, IMP-1 and VIM-2, was identified. On the basis of 2,6-dipicolinic acid (DPA), several libraries were synthesized for structure–activity relationship (SAR) analysis. Inhibitor 36 (IC50 = 80 nM) was identified to be highly selective for MBLs when compared to other Zn(II) metalloenzymes. While DPA displayed a propensity to chelate metal ions from NDM-1, 36 formed a stable NDM-1:Zn(II):inhibitor ternary complex, as demonstrated by 1H NMR, electron paramagnetic resonance (EPR) spectroscopy, equilibrium dialysis, intrinsic tryptophan fluorescence emission, and UV–vis spectroscopy. When coadministered with 36 (at concentrations nontoxic to mammalian cells), the minimum inhibitory concentrations (MICs) of imipenem against clinical isolates of Eschericia coli and Klebsiella pneumoniae harboring NDM-1 were reduced to susceptible levels.</description><subject>Anti-Bacterial Agents - chemistry</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>beta-Lactamase Inhibitors - chemistry</subject><subject>beta-Lactamase Inhibitors - pharmacology</subject><subject>beta-Lactamases - metabolism</subject><subject>Escherichia coli - drug effects</subject><subject>Escherichia coli - enzymology</subject><subject>Escherichia coli Infections - drug therapy</subject><subject>Escherichia coli Infections - microbiology</subject><subject>Humans</subject><subject>Klebsiella Infections - drug therapy</subject><subject>Klebsiella Infections - microbiology</subject><subject>Klebsiella pneumoniae - drug effects</subject><subject>Klebsiella pneumoniae - enzymology</subject><subject>Microbial Sensitivity Tests</subject><subject>Picolinic Acids - chemistry</subject><subject>Picolinic Acids - pharmacology</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kU1OHDEQha0IFCaQG0Sol9n0pOy2-2cTCTFAkICwgLVV7bYZI3d7YvcMYscVuAoHySFykhhmQMmGlWX5e89V7xHyhcKUAqPfUMXpba87Ndf9tGoBOFQfyIQKBjmvgW-RCQBjOStZsUM-xXgLAAVlxUeyw-oaGlGKCbmc2YVV3tnBquxA2S6b6WBXONqVjhnG7HSY29aOPsTMm-xC3yXAzW12rkd0zue_n3KHasQeo_7z8Ej3yLZBF_XnzblLro-Prg5_5Gc_T04PD85y5LwZc6qZaDvDyzSvqKuCFzVtGzBGVelOwXBUukPVKYNpt7LUoi45U4i0MbzjxS75vvZdLNvnFPQwBnRyEWyP4V56tPL_l8HO5Y1fSSGapqhEMvi6MQj-11LHUfY2Ku0cDtovo6QNa-q6qsoyoXyNquBjDNq8fUNBPpchUxnytQy5KSPJ9v8d8U30mn4CYA28yP0yDCmx9z3_Ai5rnBI</recordid><startdate>20170914</startdate><enddate>20170914</enddate><creator>Chen, Allie Y</creator><creator>Thomas, Pei W</creator><creator>Stewart, Alesha C</creator><creator>Bergstrom, Alexander</creator><creator>Cheng, Zishuo</creator><creator>Miller, Callie</creator><creator>Bethel, Christopher R</creator><creator>Marshall, Steven H</creator><creator>Credille, Cy V</creator><creator>Riley, Christopher L</creator><creator>Page, Richard C</creator><creator>Bonomo, Robert A</creator><creator>Crowder, Michael W</creator><creator>Tierney, David L</creator><creator>Fast, Walter</creator><creator>Cohen, Seth M</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><orcidid>https://orcid.org/0000-0002-5597-799X</orcidid><orcidid>https://orcid.org/0000-0002-3138-0283</orcidid><orcidid>https://orcid.org/0000-0001-7567-2213</orcidid><orcidid>https://orcid.org/0000-0002-5233-2280</orcidid><orcidid>https://orcid.org/0000-0002-3006-3171</orcidid><orcidid>https://orcid.org/0000-0002-3299-894X</orcidid></search><sort><creationdate>20170914</creationdate><title>Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase‑1</title><author>Chen, Allie Y ; Thomas, Pei W ; Stewart, Alesha C ; Bergstrom, Alexander ; Cheng, Zishuo ; Miller, Callie ; Bethel, Christopher R ; Marshall, Steven H ; Credille, Cy V ; Riley, Christopher L ; Page, Richard C ; Bonomo, Robert A ; Crowder, Michael W ; Tierney, David L ; Fast, Walter ; Cohen, Seth M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a449t-1e25bdf4615258734381b90ffc725810f4acedacdcfab0066e58642caa19f4d43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Anti-Bacterial Agents - chemistry</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>beta-Lactamase Inhibitors - chemistry</topic><topic>beta-Lactamase Inhibitors - pharmacology</topic><topic>beta-Lactamases - metabolism</topic><topic>Escherichia coli - drug effects</topic><topic>Escherichia coli - enzymology</topic><topic>Escherichia coli Infections - drug therapy</topic><topic>Escherichia coli Infections - microbiology</topic><topic>Humans</topic><topic>Klebsiella Infections - drug therapy</topic><topic>Klebsiella Infections - microbiology</topic><topic>Klebsiella pneumoniae - drug effects</topic><topic>Klebsiella pneumoniae - enzymology</topic><topic>Microbial Sensitivity Tests</topic><topic>Picolinic Acids - chemistry</topic><topic>Picolinic Acids - pharmacology</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Allie Y</creatorcontrib><creatorcontrib>Thomas, Pei W</creatorcontrib><creatorcontrib>Stewart, Alesha C</creatorcontrib><creatorcontrib>Bergstrom, Alexander</creatorcontrib><creatorcontrib>Cheng, Zishuo</creatorcontrib><creatorcontrib>Miller, Callie</creatorcontrib><creatorcontrib>Bethel, Christopher R</creatorcontrib><creatorcontrib>Marshall, Steven H</creatorcontrib><creatorcontrib>Credille, Cy V</creatorcontrib><creatorcontrib>Riley, Christopher L</creatorcontrib><creatorcontrib>Page, Richard C</creatorcontrib><creatorcontrib>Bonomo, Robert A</creatorcontrib><creatorcontrib>Crowder, Michael W</creatorcontrib><creatorcontrib>Tierney, David L</creatorcontrib><creatorcontrib>Fast, Walter</creatorcontrib><creatorcontrib>Cohen, Seth M</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>Chen, Allie Y</au><au>Thomas, Pei W</au><au>Stewart, Alesha C</au><au>Bergstrom, Alexander</au><au>Cheng, Zishuo</au><au>Miller, Callie</au><au>Bethel, Christopher R</au><au>Marshall, Steven H</au><au>Credille, Cy V</au><au>Riley, Christopher L</au><au>Page, Richard C</au><au>Bonomo, Robert A</au><au>Crowder, Michael W</au><au>Tierney, David L</au><au>Fast, Walter</au><au>Cohen, Seth M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase‑1</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2017-09-14</date><risdate>2017</risdate><volume>60</volume><issue>17</issue><spage>7267</spage><epage>7283</epage><pages>7267-7283</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The efficacy of β-lactam antibiotics is threatened by the emergence and global spread of metallo-β-lactamase (MBL) mediated resistance, specifically New Delhi metallo-β-lactamase-1 (NDM-1). By utilization of fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related β-lactamases, IMP-1 and VIM-2, was identified. On the basis of 2,6-dipicolinic acid (DPA), several libraries were synthesized for structure–activity relationship (SAR) analysis. Inhibitor 36 (IC50 = 80 nM) was identified to be highly selective for MBLs when compared to other Zn(II) metalloenzymes. While DPA displayed a propensity to chelate metal ions from NDM-1, 36 formed a stable NDM-1:Zn(II):inhibitor ternary complex, as demonstrated by 1H NMR, electron paramagnetic resonance (EPR) spectroscopy, equilibrium dialysis, intrinsic tryptophan fluorescence emission, and UV–vis spectroscopy. When coadministered with 36 (at concentrations nontoxic to mammalian cells), the minimum inhibitory concentrations (MICs) of imipenem against clinical isolates of Eschericia coli and Klebsiella pneumoniae harboring NDM-1 were reduced to susceptible levels.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>28809565</pmid><doi>10.1021/acs.jmedchem.7b00407</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-5597-799X</orcidid><orcidid>https://orcid.org/0000-0002-3138-0283</orcidid><orcidid>https://orcid.org/0000-0001-7567-2213</orcidid><orcidid>https://orcid.org/0000-0002-5233-2280</orcidid><orcidid>https://orcid.org/0000-0002-3006-3171</orcidid><orcidid>https://orcid.org/0000-0002-3299-894X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology beta-Lactamase Inhibitors - chemistry beta-Lactamase Inhibitors - pharmacology beta-Lactamases - metabolism Escherichia coli - drug effects Escherichia coli - enzymology Escherichia coli Infections - drug therapy Escherichia coli Infections - microbiology Humans Klebsiella Infections - drug therapy Klebsiella Infections - microbiology Klebsiella pneumoniae - drug effects Klebsiella pneumoniae - enzymology Microbial Sensitivity Tests Picolinic Acids - chemistry Picolinic Acids - pharmacology Structure-Activity Relationship |
| title | Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase‑1 |
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