Synthesis and biological evaluation of zinc chelating compounds as metallo-β-lactamase inhibitors
The syntheses of metallo-β-lactamase inhibitors comprising chelating moieties, with varying zinc affinities, and peptides partly inspired from bacterial peptide sequences, have been undertaken. The zinc chelator strength was varied using the following chelators, arranged in order of ascending bindin...
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| creator | Kildahl-Andersen, Geir Schnaars, Christian Prandina, Anthony Radix, Sylvie Le Borgne, Marc Jordheim, Lars Petter Gjøen, Tor Andresen, Adriana Magalhães Santos Lauksund, Silje Fröhlich, Christopher Samuelsen, Ørjan Rongved, Pål Åstrand, Ove Alexander Høgmoen |
| description | The syntheses of metallo-β-lactamase inhibitors comprising chelating moieties, with varying zinc affinities, and peptides partly inspired from bacterial peptide sequences, have been undertaken. The zinc chelator strength was varied using the following chelators, arranged in order of ascending binding affinity: dipicolylamine (DPA, tridentate), dipicolyl-1,2,3-triazolylmethylamine (DPTA, tetradentate) dipicolyl ethylenediamine (DPED, tetradentate) and trispicolyl ethylenediamine (TPED, pentadentate). The chosen peptides were mainly based on the known sequence of the C-terminus of the bacterial peptidoglycan precursors. Biological evaluation on clinical bacterial isolates, harbouring either the NDM-1 or VIM-2 metallo-β-lactamase, showed a clear relationship between the zinc chelator strength and restoration of meropenem activity. However, evaluation of toxicity on different cancer cell lines demonstrated a similar trend, and thus inclusion of the bacterial peptides did possess rather high toxicity towards eukaryotic cells.
New MBL inhibitor renders resistant Gram negative bacteria susceptible to carbapenems. |
| doi_str_mv | 10.1039/c8md00578h |
| format | Article |
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New MBL inhibitor renders resistant Gram negative bacteria susceptible to carbapenems.</description><subject>Affinity</subject><subject>Bacteria</subject><subject>C-Terminus</subject><subject>Cancer</subject><subject>Chelating agents</subject><subject>Chelation</subject><subject>Chemical Sciences</subject><subject>Chemistry</subject><subject>Ethylenediamine</subject><subject>Evaluation</subject><subject>Inhibitors</subject><subject>Life Sciences</subject><subject>Medication</subject><subject>Medicinal Chemistry</subject><subject>Meropenem</subject><subject>Metallo-β-lactamase</subject><subject>Metallography</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Peptides</subject><subject>Peptidoglycans</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacology</subject><subject>Restoration</subject><subject>Toxicity</subject><subject>Tumor cell lines</subject><subject>Zinc</subject><subject>Zinc compounds</subject><issn>2040-2503</issn><issn>2040-2511</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNpdkstu1DAUhiNERau2G_YgS2woUsCXXJxNpWqADtIgFsDask_siSvHHuxkpPJYPEifCQ_TDlBvbJ3z_b8vv4viOcFvCWbdO-Bjj3Hd8uFJcUJxhUtaE_L0sMbsuDhP6QbnwSjnXfWsOGYkK1pGTwr19dZPg042Iel7pGxwYW1BOqS30s1yssGjYNBP6wHBoF2u-DWCMG7C7PusSmjUk3QulHe_SidhkqNMGlk_WGWnENNZcWSkS_r8fj4tvn_88G2xLFdfrj8trlYlVA2dSmMo1ZQpWUmmWmi4kcSoxjQct5qajgI0Ta8IrWuoSQVtn2FV1UQDJQZadlpc7n03sxp1D9pPUTqxiXaU8VYEacX_HW8HsQ5b0VScVoRkg4u9wfBItrxaiV0NU9y2HcbbHfv6frMYfsw6TWK0CbRz0uswJ0EpIx1mjHUZffUIvQlz9PkpMkUwZ5jWNFNv9hTEkFLU5nACgsUuabHgn9__SXqZ4Zf_XvWAPuSagRd7ICY4dP9-FfYbxemvRA</recordid><startdate>20190401</startdate><enddate>20190401</enddate><creator>Kildahl-Andersen, Geir</creator><creator>Schnaars, Christian</creator><creator>Prandina, Anthony</creator><creator>Radix, Sylvie</creator><creator>Le Borgne, Marc</creator><creator>Jordheim, Lars Petter</creator><creator>Gjøen, Tor</creator><creator>Andresen, Adriana Magalhães Santos</creator><creator>Lauksund, Silje</creator><creator>Fröhlich, Christopher</creator><creator>Samuelsen, Ørjan</creator><creator>Rongved, Pål</creator><creator>Åstrand, Ove Alexander Høgmoen</creator><general>Royal Society of Chemistry</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QO</scope><scope>7T5</scope><scope>7T7</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>7X8</scope><scope>1XC</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5525-2614</orcidid><orcidid>https://orcid.org/0000-0003-4040-5793</orcidid><orcidid>https://orcid.org/0000-0002-3994-6157</orcidid><orcidid>https://orcid.org/0000-0002-1490-9632</orcidid><orcidid>https://orcid.org/0000-0003-1398-075X</orcidid><orcidid>https://orcid.org/0000-0003-3948-7090</orcidid></search><sort><creationdate>20190401</creationdate><title>Synthesis and biological evaluation of zinc chelating compounds as metallo-β-lactamase inhibitors</title><author>Kildahl-Andersen, Geir ; Schnaars, Christian ; Prandina, Anthony ; Radix, Sylvie ; Le Borgne, Marc ; Jordheim, Lars Petter ; Gjøen, Tor ; Andresen, Adriana Magalhães Santos ; Lauksund, Silje ; Fröhlich, Christopher ; Samuelsen, Ørjan ; Rongved, Pål ; Åstrand, Ove Alexander Høgmoen</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c462t-ff22e23ba4a3b7c68fa1fb6f6807e2f92cc66db1255c514c7d23bb451ec21fc73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Affinity</topic><topic>Bacteria</topic><topic>C-Terminus</topic><topic>Cancer</topic><topic>Chelating agents</topic><topic>Chelation</topic><topic>Chemical Sciences</topic><topic>Chemistry</topic><topic>Ethylenediamine</topic><topic>Evaluation</topic><topic>Inhibitors</topic><topic>Life Sciences</topic><topic>Medication</topic><topic>Medicinal Chemistry</topic><topic>Meropenem</topic><topic>Metallo-β-lactamase</topic><topic>Metallography</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Peptides</topic><topic>Peptidoglycans</topic><topic>Pharmaceutical sciences</topic><topic>Pharmacology</topic><topic>Restoration</topic><topic>Toxicity</topic><topic>Tumor cell lines</topic><topic>Zinc</topic><topic>Zinc compounds</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kildahl-Andersen, Geir</creatorcontrib><creatorcontrib>Schnaars, Christian</creatorcontrib><creatorcontrib>Prandina, Anthony</creatorcontrib><creatorcontrib>Radix, Sylvie</creatorcontrib><creatorcontrib>Le Borgne, Marc</creatorcontrib><creatorcontrib>Jordheim, Lars Petter</creatorcontrib><creatorcontrib>Gjøen, Tor</creatorcontrib><creatorcontrib>Andresen, Adriana Magalhães Santos</creatorcontrib><creatorcontrib>Lauksund, Silje</creatorcontrib><creatorcontrib>Fröhlich, Christopher</creatorcontrib><creatorcontrib>Samuelsen, Ørjan</creatorcontrib><creatorcontrib>Rongved, Pål</creatorcontrib><creatorcontrib>Åstrand, Ove Alexander Høgmoen</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>MedChemComm</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kildahl-Andersen, Geir</au><au>Schnaars, Christian</au><au>Prandina, Anthony</au><au>Radix, Sylvie</au><au>Le Borgne, Marc</au><au>Jordheim, Lars Petter</au><au>Gjøen, Tor</au><au>Andresen, Adriana Magalhães Santos</au><au>Lauksund, Silje</au><au>Fröhlich, Christopher</au><au>Samuelsen, Ørjan</au><au>Rongved, Pål</au><au>Åstrand, Ove Alexander Høgmoen</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and biological evaluation of zinc chelating compounds as metallo-β-lactamase inhibitors</atitle><jtitle>MedChemComm</jtitle><addtitle>Medchemcomm</addtitle><date>2019-04-01</date><risdate>2019</risdate><volume>1</volume><issue>4</issue><spage>528</spage><epage>537</epage><pages>528-537</pages><issn>2040-2503</issn><eissn>2040-2511</eissn><abstract>The syntheses of metallo-β-lactamase inhibitors comprising chelating moieties, with varying zinc affinities, and peptides partly inspired from bacterial peptide sequences, have been undertaken. The zinc chelator strength was varied using the following chelators, arranged in order of ascending binding affinity: dipicolylamine (DPA, tridentate), dipicolyl-1,2,3-triazolylmethylamine (DPTA, tetradentate) dipicolyl ethylenediamine (DPED, tetradentate) and trispicolyl ethylenediamine (TPED, pentadentate). The chosen peptides were mainly based on the known sequence of the C-terminus of the bacterial peptidoglycan precursors. Biological evaluation on clinical bacterial isolates, harbouring either the NDM-1 or VIM-2 metallo-β-lactamase, showed a clear relationship between the zinc chelator strength and restoration of meropenem activity. However, evaluation of toxicity on different cancer cell lines demonstrated a similar trend, and thus inclusion of the bacterial peptides did possess rather high toxicity towards eukaryotic cells.
New MBL inhibitor renders resistant Gram negative bacteria susceptible to carbapenems.</abstract><cop>England</cop><pub>Royal Society of Chemistry</pub><pmid>31057732</pmid><doi>10.1039/c8md00578h</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-5525-2614</orcidid><orcidid>https://orcid.org/0000-0003-4040-5793</orcidid><orcidid>https://orcid.org/0000-0002-3994-6157</orcidid><orcidid>https://orcid.org/0000-0002-1490-9632</orcidid><orcidid>https://orcid.org/0000-0003-1398-075X</orcidid><orcidid>https://orcid.org/0000-0003-3948-7090</orcidid><oa>free_for_read</oa></addata></record> |
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| source | PubMed (Medline); Royal Society Of Chemistry Journals 2008- |
| subjects | Affinity Bacteria C-Terminus Cancer Chelating agents Chelation Chemical Sciences Chemistry Ethylenediamine Evaluation Inhibitors Life Sciences Medication Medicinal Chemistry Meropenem Metallo-β-lactamase Metallography NMR Nuclear magnetic resonance Peptides Peptidoglycans Pharmaceutical sciences Pharmacology Restoration Toxicity Tumor cell lines Zinc Zinc compounds |
| title | Synthesis and biological evaluation of zinc chelating compounds as metallo-β-lactamase inhibitors |
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