Inhibition of the Antibacterial Target UDP-(3-O-acyl)-N-acetylglucosamine Deacetylase (LpxC): Isoxazoline Zinc Amidase Inhibitors Bearing Diverse Metal Binding Groups
UDP-3-O-[R-3-hydroxymyristoyl]-GlcNAc deacetylase (LpxC) is a zinc amidase that catalyzes the second step of lipid A biosynthesis in Gram negative bacteria. Known inhibitors of this enzyme are oxazolines incorporating a hydroxamic acid at the 4-position, which is believed to coordinate to the single...
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| Veröffentlicht in: | Journal of medicinal chemistry 2002-09, Vol.45 (19), p.4359-4370 |
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| container_issue | 19 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 45 |
| creator | Pirrung, Michael C Tumey, L. Nathan Raetz, Christian R. H Jackman, Jane E Snehalatha, Karnem McClerren, Amanda L Fierke, Carol A Gantt, Stephanie L Rusche, Kristin M |
| description | UDP-3-O-[R-3-hydroxymyristoyl]-GlcNAc deacetylase (LpxC) is a zinc amidase that catalyzes the second step of lipid A biosynthesis in Gram negative bacteria. Known inhibitors of this enzyme are oxazolines incorporating a hydroxamic acid at the 4-position, which is believed to coordinate to the single essential zinc ion. A new structural class of inhibitors was designed to incorporate a more stable and more synthetically versatile isoxazoline core. The synthetic versatility of the isoxazoline allowed for a broad study of metal binding groups. Nine of 17 isoxazolines, each incorporating a different potential metal binding functional group, were found to exhibit enzyme inhibitory activity, including one that is more active than the corresponding hydroxamic acid. Additionally, a designed affinity label inhibits LpxC in a time-dependent manner. |
| doi_str_mv | 10.1021/jm020183v |
| format | Article |
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Nathan ; Raetz, Christian R. H ; Jackman, Jane E ; Snehalatha, Karnem ; McClerren, Amanda L ; Fierke, Carol A ; Gantt, Stephanie L ; Rusche, Kristin M</creator><creatorcontrib>Pirrung, Michael C ; Tumey, L. Nathan ; Raetz, Christian R. H ; Jackman, Jane E ; Snehalatha, Karnem ; McClerren, Amanda L ; Fierke, Carol A ; Gantt, Stephanie L ; Rusche, Kristin M</creatorcontrib><description>UDP-3-O-[R-3-hydroxymyristoyl]-GlcNAc deacetylase (LpxC) is a zinc amidase that catalyzes the second step of lipid A biosynthesis in Gram negative bacteria. Known inhibitors of this enzyme are oxazolines incorporating a hydroxamic acid at the 4-position, which is believed to coordinate to the single essential zinc ion. A new structural class of inhibitors was designed to incorporate a more stable and more synthetically versatile isoxazoline core. The synthetic versatility of the isoxazoline allowed for a broad study of metal binding groups. Nine of 17 isoxazolines, each incorporating a different potential metal binding functional group, were found to exhibit enzyme inhibitory activity, including one that is more active than the corresponding hydroxamic acid. Additionally, a designed affinity label inhibits LpxC in a time-dependent manner.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm020183v</identifier><identifier>PMID: 12213077</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Amidohydrolases - antagonists & inhibitors ; Amidohydrolases - metabolism ; Anti-Bacterial Agents - chemical synthesis ; Anti-Bacterial Agents - chemistry ; Anti-Bacterial Agents - pharmacology ; Antibacterial agents ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Biological and medical sciences ; Colony Count, Microbial ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - chemistry ; Enzyme Inhibitors - pharmacology ; Escherichia coli - drug effects ; Hydroxamic Acids - pharmacology ; Inhibitory Concentration 50 ; Isoxazoles - chemical synthesis ; Isoxazoles - chemistry ; Isoxazoles - pharmacology ; isoxazoline zinc amidase ; lipid A ; LpxC protein ; Medical sciences ; Microbial Sensitivity Tests ; Models, Molecular ; N-acetylglucosamine deacetylase ; Pharmacology. 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Nathan</creatorcontrib><creatorcontrib>Raetz, Christian R. H</creatorcontrib><creatorcontrib>Jackman, Jane E</creatorcontrib><creatorcontrib>Snehalatha, Karnem</creatorcontrib><creatorcontrib>McClerren, Amanda L</creatorcontrib><creatorcontrib>Fierke, Carol A</creatorcontrib><creatorcontrib>Gantt, Stephanie L</creatorcontrib><creatorcontrib>Rusche, Kristin M</creatorcontrib><title>Inhibition of the Antibacterial Target UDP-(3-O-acyl)-N-acetylglucosamine Deacetylase (LpxC): Isoxazoline Zinc Amidase Inhibitors Bearing Diverse Metal Binding Groups</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>UDP-3-O-[R-3-hydroxymyristoyl]-GlcNAc deacetylase (LpxC) is a zinc amidase that catalyzes the second step of lipid A biosynthesis in Gram negative bacteria. Known inhibitors of this enzyme are oxazolines incorporating a hydroxamic acid at the 4-position, which is believed to coordinate to the single essential zinc ion. A new structural class of inhibitors was designed to incorporate a more stable and more synthetically versatile isoxazoline core. The synthetic versatility of the isoxazoline allowed for a broad study of metal binding groups. Nine of 17 isoxazolines, each incorporating a different potential metal binding functional group, were found to exhibit enzyme inhibitory activity, including one that is more active than the corresponding hydroxamic acid. Additionally, a designed affinity label inhibits LpxC in a time-dependent manner.</description><subject>Amidohydrolases - antagonists & inhibitors</subject><subject>Amidohydrolases - 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>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Biological and medical sciences</subject><subject>Colony Count, Microbial</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Escherichia coli - drug effects</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Inhibitory Concentration 50</subject><subject>Isoxazoles - chemical synthesis</subject><subject>Isoxazoles - chemistry</subject><subject>Isoxazoles - pharmacology</subject><subject>isoxazoline zinc amidase</subject><subject>lipid A</subject><subject>LpxC protein</subject><subject>Medical sciences</subject><subject>Microbial Sensitivity Tests</subject><subject>Models, Molecular</subject><subject>N-acetylglucosamine deacetylase</subject><subject>Pharmacology. Drug treatments</subject><subject>Structure-Activity Relationship</subject><subject>Zinc - metabolism</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkc-O0zAQxi0EYsvCgRdAvoC2B4P_JE3CrdvCUtRlV6IrIS7WxHG67iZ2sZNVy4krj8Jr8SQkarS9IB9Gmvnp-2b8IfSS0beMcvZuU1NOWSruH6ERizklUUqjx2hEKeeET7g4Qc9C2FBKBePiKTphnDNBk2SE_izsrclNY5zFrsTNrcZT25gcVKO9gQqvwK91g2_m1-RMkCsCal-NyZeu6mZfratWuQC1sRrP9aEHQeOz5XY3G7__--s3XgS3g5-u6pHvxio8rU3RM4Oz8wGfa_DGrvHc3GvfjS5101mfG1v03Qvv2m14jp6UUAX9Yqin6Objh9XsE1leXSxm0yUBkbGGpN2VtOQQpWlOk4KpnBWQFIUAlfMoT6GIRXc7ywsV60kUl2lSZpMiS0uR6ZwJcYreHHS33v1odWhkbYLSVQVWuzZIlnUvSngHjg-g8i4Er0u59aYGv5eMyj4X-ZBLx74aRNu81sWRHILogNcDAEFBVXqwyoQjJ9IsZpPelBw4Exq9e5iDv5OTRCSxXF1_lZ-jy1kqsm9yddQFFeTGtd52f_efBf8BY7uySA</recordid><startdate>20020912</startdate><enddate>20020912</enddate><creator>Pirrung, Michael C</creator><creator>Tumey, L. Nathan</creator><creator>Raetz, Christian R. H</creator><creator>Jackman, Jane E</creator><creator>Snehalatha, Karnem</creator><creator>McClerren, Amanda L</creator><creator>Fierke, Carol A</creator><creator>Gantt, Stephanie L</creator><creator>Rusche, Kristin M</creator><general>American Chemical Society</general><scope>BSCLL</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>7QL</scope><scope>C1K</scope></search><sort><creationdate>20020912</creationdate><title>Inhibition of the Antibacterial Target UDP-(3-O-acyl)-N-acetylglucosamine Deacetylase (LpxC): Isoxazoline Zinc Amidase Inhibitors Bearing Diverse Metal Binding Groups</title><author>Pirrung, Michael C ; Tumey, L. Nathan ; Raetz, Christian R. H ; Jackman, Jane E ; Snehalatha, Karnem ; McClerren, Amanda L ; Fierke, Carol A ; Gantt, Stephanie L ; Rusche, Kristin M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a391t-80000f2a488b07d1cb1da7dd3acb24b8ad531301bdc5e645f87f96d98f39eb133</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Amidohydrolases - antagonists & inhibitors</topic><topic>Amidohydrolases - 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>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Biological and medical sciences</topic><topic>Colony Count, Microbial</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Escherichia coli - drug effects</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Inhibitory Concentration 50</topic><topic>Isoxazoles - chemical synthesis</topic><topic>Isoxazoles - chemistry</topic><topic>Isoxazoles - pharmacology</topic><topic>isoxazoline zinc amidase</topic><topic>lipid A</topic><topic>LpxC protein</topic><topic>Medical sciences</topic><topic>Microbial Sensitivity Tests</topic><topic>Models, Molecular</topic><topic>N-acetylglucosamine deacetylase</topic><topic>Pharmacology. Drug treatments</topic><topic>Structure-Activity Relationship</topic><topic>Zinc - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pirrung, Michael C</creatorcontrib><creatorcontrib>Tumey, L. Nathan</creatorcontrib><creatorcontrib>Raetz, Christian R. 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H</au><au>Jackman, Jane E</au><au>Snehalatha, Karnem</au><au>McClerren, Amanda L</au><au>Fierke, Carol A</au><au>Gantt, Stephanie L</au><au>Rusche, Kristin M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of the Antibacterial Target UDP-(3-O-acyl)-N-acetylglucosamine Deacetylase (LpxC): Isoxazoline Zinc Amidase Inhibitors Bearing Diverse Metal Binding Groups</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2002-09-12</date><risdate>2002</risdate><volume>45</volume><issue>19</issue><spage>4359</spage><epage>4370</epage><pages>4359-4370</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>UDP-3-O-[R-3-hydroxymyristoyl]-GlcNAc deacetylase (LpxC) is a zinc amidase that catalyzes the second step of lipid A biosynthesis in Gram negative bacteria. Known inhibitors of this enzyme are oxazolines incorporating a hydroxamic acid at the 4-position, which is believed to coordinate to the single essential zinc ion. A new structural class of inhibitors was designed to incorporate a more stable and more synthetically versatile isoxazoline core. The synthetic versatility of the isoxazoline allowed for a broad study of metal binding groups. Nine of 17 isoxazolines, each incorporating a different potential metal binding functional group, were found to exhibit enzyme inhibitory activity, including one that is more active than the corresponding hydroxamic acid. Additionally, a designed affinity label inhibits LpxC in a time-dependent manner.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>12213077</pmid><doi>10.1021/jm020183v</doi><tpages>12</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2002-09, Vol.45 (19), p.4359-4370 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; ACS Publications |
| subjects | Amidohydrolases - antagonists & inhibitors Amidohydrolases - metabolism Anti-Bacterial Agents - chemical synthesis Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Antibacterial agents Antibiotics. Antiinfectious agents. Antiparasitic agents Biological and medical sciences Colony Count, Microbial Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology Escherichia coli - drug effects Hydroxamic Acids - pharmacology Inhibitory Concentration 50 Isoxazoles - chemical synthesis Isoxazoles - chemistry Isoxazoles - pharmacology isoxazoline zinc amidase lipid A LpxC protein Medical sciences Microbial Sensitivity Tests Models, Molecular N-acetylglucosamine deacetylase Pharmacology. Drug treatments Structure-Activity Relationship Zinc - metabolism |
| title | Inhibition of the Antibacterial Target UDP-(3-O-acyl)-N-acetylglucosamine Deacetylase (LpxC): Isoxazoline Zinc Amidase Inhibitors Bearing Diverse Metal Binding Groups |
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