Two Distinct Mechanisms of Inhibition of LpxA Acyltransferase Essential for Lipopolysaccharide Biosynthesis
The lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multi-drug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds 1 and 2) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharid...
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| Veröffentlicht in: | Journal of the American Chemical Society 2020-03, Vol.142 (9), p.4445-4455 |
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| creator | Han, Wooseok Ma, Xiaolei Balibar, Carl J Baxter Rath, Christopher M Benton, Bret Bermingham, Alun Casey, Fergal Chie-Leon, Barbara Cho, Min-Kyu Frank, Andreas O Frommlet, Alexandra Ho, Chi-Min Lee, Patrick S Li, Min Lingel, Andreas Ma, Sylvia Merritt, Hanne Ornelas, Elizabeth De Pascale, Gianfranco Prathapam, Ramadevi Prosen, Katherine R Rasper, Dita Ruzin, Alexey Sawyer, William S Shaul, Jacob Shen, Xiaoyu Shia, Steven Steffek, Micah Subramanian, Sharadha Vo, Jason Wang, Feng Wartchow, Charles Uehara, Tsuyoshi |
| description | The lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multi-drug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds 1 and 2) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharide biosynthesis pathway. We show genetically that the antibacterial activities of the compounds against efflux-deficient Escherichia coli are mediated by LpxA inhibition. Consistently, the compounds inhibited the LpxA enzymatic reaction in vitro. Intriguingly, using biochemical, biophysical, and structural characterization, we reveal two distinct mechanisms of LpxA inhibition; compound 1 is a substrate-competitive inhibitor targeting apo LpxA, and compound 2 is an uncompetitive inhibitor targeting the LpxA/product complex. Compound 2 exhibited more favorable biological and physicochemical properties than compound 1 and was optimized using structural information to achieve improved antibacterial activity against wild-type E. coli. These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme/product complexes in drug discovery. |
| doi_str_mv | 10.1021/jacs.9b13530 |
| format | Article |
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Here, we report two novel small-molecule inhibitors (compounds 1 and 2) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharide biosynthesis pathway. We show genetically that the antibacterial activities of the compounds against efflux-deficient Escherichia coli are mediated by LpxA inhibition. Consistently, the compounds inhibited the LpxA enzymatic reaction in vitro. Intriguingly, using biochemical, biophysical, and structural characterization, we reveal two distinct mechanisms of LpxA inhibition; compound 1 is a substrate-competitive inhibitor targeting apo LpxA, and compound 2 is an uncompetitive inhibitor targeting the LpxA/product complex. Compound 2 exhibited more favorable biological and physicochemical properties than compound 1 and was optimized using structural information to achieve improved antibacterial activity against wild-type E. coli. These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme/product complexes in drug discovery.</description><identifier>ISSN: 0002-7863</identifier><identifier>EISSN: 1520-5126</identifier><identifier>DOI: 10.1021/jacs.9b13530</identifier><identifier>PMID: 32064871</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Acyltransferases - antagonists & inhibitors ; Acyltransferases - metabolism ; Anti-Bacterial Agents - metabolism ; Anti-Bacterial Agents - pharmacology ; Crystallography, X-Ray ; Enzyme Inhibitors - metabolism ; Enzyme Inhibitors - pharmacology ; Escherichia coli - drug effects ; Escherichia coli - enzymology ; Imidazoles - metabolism ; Imidazoles - pharmacology ; Microbial Sensitivity Tests ; Protein Binding ; Pyrazoles - metabolism ; Pyrazoles - pharmacology</subject><ispartof>Journal of the American Chemical Society, 2020-03, Vol.142 (9), p.4445-4455</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a361t-911b46d31ed55e6a5d5e90e4bac061917a35a7d46d4b60a9dc4d87431bbd2a413</citedby><cites>FETCH-LOGICAL-a361t-911b46d31ed55e6a5d5e90e4bac061917a35a7d46d4b60a9dc4d87431bbd2a413</cites><orcidid>0000-0001-6994-4286 ; 0000-0002-5307-827X ; 0000-0003-2909-4920</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/jacs.9b13530$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jacs.9b13530$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,777,781,2752,27057,27905,27906,56719,56769</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32064871$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Han, Wooseok</creatorcontrib><creatorcontrib>Ma, Xiaolei</creatorcontrib><creatorcontrib>Balibar, Carl J</creatorcontrib><creatorcontrib>Baxter Rath, Christopher M</creatorcontrib><creatorcontrib>Benton, Bret</creatorcontrib><creatorcontrib>Bermingham, Alun</creatorcontrib><creatorcontrib>Casey, Fergal</creatorcontrib><creatorcontrib>Chie-Leon, Barbara</creatorcontrib><creatorcontrib>Cho, Min-Kyu</creatorcontrib><creatorcontrib>Frank, Andreas O</creatorcontrib><creatorcontrib>Frommlet, Alexandra</creatorcontrib><creatorcontrib>Ho, Chi-Min</creatorcontrib><creatorcontrib>Lee, Patrick S</creatorcontrib><creatorcontrib>Li, Min</creatorcontrib><creatorcontrib>Lingel, Andreas</creatorcontrib><creatorcontrib>Ma, Sylvia</creatorcontrib><creatorcontrib>Merritt, Hanne</creatorcontrib><creatorcontrib>Ornelas, Elizabeth</creatorcontrib><creatorcontrib>De Pascale, Gianfranco</creatorcontrib><creatorcontrib>Prathapam, Ramadevi</creatorcontrib><creatorcontrib>Prosen, Katherine R</creatorcontrib><creatorcontrib>Rasper, Dita</creatorcontrib><creatorcontrib>Ruzin, Alexey</creatorcontrib><creatorcontrib>Sawyer, William S</creatorcontrib><creatorcontrib>Shaul, Jacob</creatorcontrib><creatorcontrib>Shen, Xiaoyu</creatorcontrib><creatorcontrib>Shia, Steven</creatorcontrib><creatorcontrib>Steffek, Micah</creatorcontrib><creatorcontrib>Subramanian, Sharadha</creatorcontrib><creatorcontrib>Vo, Jason</creatorcontrib><creatorcontrib>Wang, Feng</creatorcontrib><creatorcontrib>Wartchow, Charles</creatorcontrib><creatorcontrib>Uehara, Tsuyoshi</creatorcontrib><title>Two Distinct Mechanisms of Inhibition of LpxA Acyltransferase Essential for Lipopolysaccharide Biosynthesis</title><title>Journal of the American Chemical Society</title><addtitle>J. Am. Chem. Soc</addtitle><description>The lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multi-drug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds 1 and 2) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharide biosynthesis pathway. We show genetically that the antibacterial activities of the compounds against efflux-deficient Escherichia coli are mediated by LpxA inhibition. Consistently, the compounds inhibited the LpxA enzymatic reaction in vitro. Intriguingly, using biochemical, biophysical, and structural characterization, we reveal two distinct mechanisms of LpxA inhibition; compound 1 is a substrate-competitive inhibitor targeting apo LpxA, and compound 2 is an uncompetitive inhibitor targeting the LpxA/product complex. Compound 2 exhibited more favorable biological and physicochemical properties than compound 1 and was optimized using structural information to achieve improved antibacterial activity against wild-type E. coli. These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme/product complexes in drug discovery.</description><subject>Acyltransferases - antagonists & inhibitors</subject><subject>Acyltransferases - metabolism</subject><subject>Anti-Bacterial Agents - metabolism</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Crystallography, X-Ray</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Escherichia coli - drug effects</subject><subject>Escherichia coli - enzymology</subject><subject>Imidazoles - metabolism</subject><subject>Imidazoles - pharmacology</subject><subject>Microbial Sensitivity Tests</subject><subject>Protein Binding</subject><subject>Pyrazoles - metabolism</subject><subject>Pyrazoles - pharmacology</subject><issn>0002-7863</issn><issn>1520-5126</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkD1PwzAQhi0EgvKxMSOPDAR88UeasZRPqYgF5sixHdUltYMvFfTfk4oCC9PplZ57TvcScgrsElgOVwtt8LKsgUvOdsgIZM4yCbnaJSPGWJ4VY8UPyCHiYogiH8M-OeA5U2JcwIi8vXxEeuOx98H09MmZuQ4el0hjQx_D3Ne-9zFs0qz7nNCJWbd90gEblzQ6eovoQu91S5uY6Mx3sYvtGrUZPMlbR699xHXo5w49HpO9RrfoTrbziLze3b5MH7LZ8_3jdDLLNFfQZyVALZTl4KyUTmlppSuZE7U2TEEJheZSF3ZARK2YLq0RdlwIDnVtcy2AH5Hzb2-X4vvKYV8tPRrXtjq4uMIq51IpkKIsBvTiGzUpIibXVF3yS53WFbBqU2-1qbfa1jvgZ1vzql46-wv_9Pl3erO1iKsUhkf_d30Bk9SE4w</recordid><startdate>20200304</startdate><enddate>20200304</enddate><creator>Han, Wooseok</creator><creator>Ma, Xiaolei</creator><creator>Balibar, Carl J</creator><creator>Baxter Rath, Christopher M</creator><creator>Benton, Bret</creator><creator>Bermingham, Alun</creator><creator>Casey, Fergal</creator><creator>Chie-Leon, Barbara</creator><creator>Cho, Min-Kyu</creator><creator>Frank, Andreas O</creator><creator>Frommlet, Alexandra</creator><creator>Ho, Chi-Min</creator><creator>Lee, Patrick S</creator><creator>Li, Min</creator><creator>Lingel, Andreas</creator><creator>Ma, Sylvia</creator><creator>Merritt, Hanne</creator><creator>Ornelas, Elizabeth</creator><creator>De Pascale, Gianfranco</creator><creator>Prathapam, Ramadevi</creator><creator>Prosen, Katherine R</creator><creator>Rasper, Dita</creator><creator>Ruzin, Alexey</creator><creator>Sawyer, William S</creator><creator>Shaul, Jacob</creator><creator>Shen, Xiaoyu</creator><creator>Shia, Steven</creator><creator>Steffek, Micah</creator><creator>Subramanian, Sharadha</creator><creator>Vo, Jason</creator><creator>Wang, Feng</creator><creator>Wartchow, Charles</creator><creator>Uehara, Tsuyoshi</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><orcidid>https://orcid.org/0000-0001-6994-4286</orcidid><orcidid>https://orcid.org/0000-0002-5307-827X</orcidid><orcidid>https://orcid.org/0000-0003-2909-4920</orcidid></search><sort><creationdate>20200304</creationdate><title>Two Distinct Mechanisms of Inhibition of LpxA Acyltransferase Essential for Lipopolysaccharide Biosynthesis</title><author>Han, Wooseok ; 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Am. Chem. Soc</addtitle><date>2020-03-04</date><risdate>2020</risdate><volume>142</volume><issue>9</issue><spage>4445</spage><epage>4455</epage><pages>4445-4455</pages><issn>0002-7863</issn><eissn>1520-5126</eissn><abstract>The lipopolysaccharide biosynthesis pathway is considered an attractive drug target against the rising threat of multi-drug-resistant Gram-negative bacteria. Here, we report two novel small-molecule inhibitors (compounds 1 and 2) of the acyltransferase LpxA, the first enzyme in the lipopolysaccharide biosynthesis pathway. We show genetically that the antibacterial activities of the compounds against efflux-deficient Escherichia coli are mediated by LpxA inhibition. Consistently, the compounds inhibited the LpxA enzymatic reaction in vitro. Intriguingly, using biochemical, biophysical, and structural characterization, we reveal two distinct mechanisms of LpxA inhibition; compound 1 is a substrate-competitive inhibitor targeting apo LpxA, and compound 2 is an uncompetitive inhibitor targeting the LpxA/product complex. Compound 2 exhibited more favorable biological and physicochemical properties than compound 1 and was optimized using structural information to achieve improved antibacterial activity against wild-type E. coli. These results show that LpxA is a promising antibacterial target and imply the advantages of targeting enzyme/product complexes in drug discovery.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>32064871</pmid><doi>10.1021/jacs.9b13530</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-6994-4286</orcidid><orcidid>https://orcid.org/0000-0002-5307-827X</orcidid><orcidid>https://orcid.org/0000-0003-2909-4920</orcidid></addata></record> |
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| ispartof | Journal of the American Chemical Society, 2020-03, Vol.142 (9), p.4445-4455 |
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| subjects | Acyltransferases - antagonists & inhibitors Acyltransferases - metabolism Anti-Bacterial Agents - metabolism Anti-Bacterial Agents - pharmacology Crystallography, X-Ray Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacology Escherichia coli - drug effects Escherichia coli - enzymology Imidazoles - metabolism Imidazoles - pharmacology Microbial Sensitivity Tests Protein Binding Pyrazoles - metabolism Pyrazoles - pharmacology |
| title | Two Distinct Mechanisms of Inhibition of LpxA Acyltransferase Essential for Lipopolysaccharide Biosynthesis |
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