Bis(benzoyl) phosphate inactivators of beta-lactamase C from Mtb
[Display omitted] The class A β-lactamase BlaC is a cell surface expressed serine hydrolase of Mycobacterium tuberculosis (Mtb), one of the causative agents for Tuberculosis in humans. Mtb has demonstrated increased susceptibility to β-lactam antibiotics upon inactivation of BlaC; thus, making BlaC...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2019-08, Vol.29 (16), p.2116-2118 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 29 |
| creator | White, Dawanna S. Choy, Cindy J. Moural, Timothy W. Martin, Stacy E. Wang, Jing Gargaro, Samantha Kang, ChulHee Berkman, Clifford E. |
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The class A β-lactamase BlaC is a cell surface expressed serine hydrolase of Mycobacterium tuberculosis (Mtb), one of the causative agents for Tuberculosis in humans. Mtb has demonstrated increased susceptibility to β-lactam antibiotics upon inactivation of BlaC; thus, making BlaC a rational enzyme target for therapeutic agents. Herein, we present the synthesis and structure-activity-relationship data for the 1st-generation library of bis(benzoyl) phosphates (1–10). Substituent effects ranged from σp = −0.27 to 0.78 for electronic and π = −0.41 to 1.98 for hydrophobic parameters. Compounds 1, 4 and 5 demonstrated the greatest inhibitory potency against BlaC in a time-dependent manner (kobs = 0.212, 0.324, and 0.450 mn−1 respectively). Combined crystal structure data and mass spectrometric analysis of a tryptic digest for BlaC inactivated with 4 provided evidence that the mechanism of inactivation by this bis(benzoyl) phosphate scaffold occurs via phosphorylation of the active-site Ser-70, ultimately leading to an aged form of the enzyme. |
| doi_str_mv | 10.1016/j.bmcl.2019.07.002 |
| format | Article |
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The class A β-lactamase BlaC is a cell surface expressed serine hydrolase of Mycobacterium tuberculosis (Mtb), one of the causative agents for Tuberculosis in humans. Mtb has demonstrated increased susceptibility to β-lactam antibiotics upon inactivation of BlaC; thus, making BlaC a rational enzyme target for therapeutic agents. Herein, we present the synthesis and structure-activity-relationship data for the 1st-generation library of bis(benzoyl) phosphates (1–10). Substituent effects ranged from σp = −0.27 to 0.78 for electronic and π = −0.41 to 1.98 for hydrophobic parameters. Compounds 1, 4 and 5 demonstrated the greatest inhibitory potency against BlaC in a time-dependent manner (kobs = 0.212, 0.324, and 0.450 mn−1 respectively). Combined crystal structure data and mass spectrometric analysis of a tryptic digest for BlaC inactivated with 4 provided evidence that the mechanism of inactivation by this bis(benzoyl) phosphate scaffold occurs via phosphorylation of the active-site Ser-70, ultimately leading to an aged form of the enzyme.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2019.07.002</identifier><identifier>PMID: 31281019</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Beta-lactamase ; BlaC ; Inhibition ; Phosphorylation ; Tuberculosis</subject><ispartof>Bioorganic & medicinal chemistry letters, 2019-08, Vol.29 (16), p.2116-2118</ispartof><rights>2019 Elsevier Ltd</rights><rights>Copyright © 2019 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c406t-a3f0d0d878789582501457d240ed25927a25042c8d2e0dc99fd310efb3ad40c03</cites><orcidid>0000-0001-7518-3591</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bmcl.2019.07.002$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3541,27915,27916,45986</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31281019$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>White, Dawanna S.</creatorcontrib><creatorcontrib>Choy, Cindy J.</creatorcontrib><creatorcontrib>Moural, Timothy W.</creatorcontrib><creatorcontrib>Martin, Stacy E.</creatorcontrib><creatorcontrib>Wang, Jing</creatorcontrib><creatorcontrib>Gargaro, Samantha</creatorcontrib><creatorcontrib>Kang, ChulHee</creatorcontrib><creatorcontrib>Berkman, Clifford E.</creatorcontrib><title>Bis(benzoyl) phosphate inactivators of beta-lactamase C from Mtb</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
The class A β-lactamase BlaC is a cell surface expressed serine hydrolase of Mycobacterium tuberculosis (Mtb), one of the causative agents for Tuberculosis in humans. Mtb has demonstrated increased susceptibility to β-lactam antibiotics upon inactivation of BlaC; thus, making BlaC a rational enzyme target for therapeutic agents. Herein, we present the synthesis and structure-activity-relationship data for the 1st-generation library of bis(benzoyl) phosphates (1–10). Substituent effects ranged from σp = −0.27 to 0.78 for electronic and π = −0.41 to 1.98 for hydrophobic parameters. Compounds 1, 4 and 5 demonstrated the greatest inhibitory potency against BlaC in a time-dependent manner (kobs = 0.212, 0.324, and 0.450 mn−1 respectively). Combined crystal structure data and mass spectrometric analysis of a tryptic digest for BlaC inactivated with 4 provided evidence that the mechanism of inactivation by this bis(benzoyl) phosphate scaffold occurs via phosphorylation of the active-site Ser-70, ultimately leading to an aged form of the enzyme.</description><subject>Beta-lactamase</subject><subject>BlaC</subject><subject>Inhibition</subject><subject>Phosphorylation</subject><subject>Tuberculosis</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp9kE1r3DAQhkVpSLZp_kAPxcfkYGf05Q8Ipc3SJIWUXlroTcjSuKvFtjaSdiH99dWyaWguZQ4Do3ceDQ8h7yhUFGh9ua76yYwVA9pV0FQA7BVZUFGLkguQr8kCuhrKthM_T8ibGNcAVIAQx-SEU9ZmRLcgH69dPO9x_u0fx4tis_Jxs9IJCzdrk9xOJx9i4Yeix6TLMc_0pCMWy2IIfiq-pv4tORr0GPHsqZ-SHzefvy_vyvtvt1-Wn-5LI6BOpeYDWLBtk6uTLZP5FtlYJgAtkx1rdB4JZlrLEKzpusFyCjj0XFsBBvgp-XDgbrb9hNbgnIIe1Sa4SYdH5bVTL19mt1K__E41tRSS8gw4fwIE_7DFmNTkosFx1DP6bVSMSd5yLmWdo-wQNcHHGHB4_oaC2qtXa7VXr_bqFTQqq89L7_898Hnlr-scuDoEMGvaOQwqGoezQesCmqSsd__j_wHz8pTe</recordid><startdate>20190815</startdate><enddate>20190815</enddate><creator>White, Dawanna S.</creator><creator>Choy, Cindy J.</creator><creator>Moural, Timothy W.</creator><creator>Martin, Stacy E.</creator><creator>Wang, Jing</creator><creator>Gargaro, Samantha</creator><creator>Kang, ChulHee</creator><creator>Berkman, Clifford E.</creator><general>Elsevier Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-7518-3591</orcidid></search><sort><creationdate>20190815</creationdate><title>Bis(benzoyl) phosphate inactivators of beta-lactamase C from Mtb</title><author>White, Dawanna S. ; Choy, Cindy J. ; Moural, Timothy W. ; Martin, Stacy E. ; Wang, Jing ; Gargaro, Samantha ; Kang, ChulHee ; Berkman, Clifford E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c406t-a3f0d0d878789582501457d240ed25927a25042c8d2e0dc99fd310efb3ad40c03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Beta-lactamase</topic><topic>BlaC</topic><topic>Inhibition</topic><topic>Phosphorylation</topic><topic>Tuberculosis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>White, Dawanna S.</creatorcontrib><creatorcontrib>Choy, Cindy J.</creatorcontrib><creatorcontrib>Moural, Timothy W.</creatorcontrib><creatorcontrib>Martin, Stacy E.</creatorcontrib><creatorcontrib>Wang, Jing</creatorcontrib><creatorcontrib>Gargaro, Samantha</creatorcontrib><creatorcontrib>Kang, ChulHee</creatorcontrib><creatorcontrib>Berkman, Clifford E.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>White, Dawanna S.</au><au>Choy, Cindy J.</au><au>Moural, Timothy W.</au><au>Martin, Stacy E.</au><au>Wang, Jing</au><au>Gargaro, Samantha</au><au>Kang, ChulHee</au><au>Berkman, Clifford E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bis(benzoyl) phosphate inactivators of beta-lactamase C from Mtb</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2019-08-15</date><risdate>2019</risdate><volume>29</volume><issue>16</issue><spage>2116</spage><epage>2118</epage><pages>2116-2118</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
The class A β-lactamase BlaC is a cell surface expressed serine hydrolase of Mycobacterium tuberculosis (Mtb), one of the causative agents for Tuberculosis in humans. Mtb has demonstrated increased susceptibility to β-lactam antibiotics upon inactivation of BlaC; thus, making BlaC a rational enzyme target for therapeutic agents. Herein, we present the synthesis and structure-activity-relationship data for the 1st-generation library of bis(benzoyl) phosphates (1–10). Substituent effects ranged from σp = −0.27 to 0.78 for electronic and π = −0.41 to 1.98 for hydrophobic parameters. Compounds 1, 4 and 5 demonstrated the greatest inhibitory potency against BlaC in a time-dependent manner (kobs = 0.212, 0.324, and 0.450 mn−1 respectively). Combined crystal structure data and mass spectrometric analysis of a tryptic digest for BlaC inactivated with 4 provided evidence that the mechanism of inactivation by this bis(benzoyl) phosphate scaffold occurs via phosphorylation of the active-site Ser-70, ultimately leading to an aged form of the enzyme.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>31281019</pmid><doi>10.1016/j.bmcl.2019.07.002</doi><tpages>3</tpages><orcidid>https://orcid.org/0000-0001-7518-3591</orcidid><oa>free_for_read</oa></addata></record> |
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| language | eng |
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| source | ScienceDirect Journals (5 years ago - present) |
| subjects | Beta-lactamase BlaC Inhibition Phosphorylation Tuberculosis |
| title | Bis(benzoyl) phosphate inactivators of beta-lactamase C from Mtb |
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