{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T01:36:00Z","timestamp":1791596160439,"version":"4.3.4"},"reference-count":44,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T00:00:00Z","timestamp":1614729600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["725523"],"award-info":[{"award-number":["725523"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2021,5,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Metallo\u2010\u03b2\u2010lactamases (MBLs) are zinc\u2010dependent bacterial enzymes that inactivate essentially all classes of \u03b2\u2010lactam antibiotics including last\u2010resort carbapenems. At present there are no clinically approved MBL inhibitors, and in order to develop such agents it is essential to understand their inhibitory mechanisms. Herein, we describe a comprehensive mechanistic study of a panel of structurally distinct MBL inhibitors reported in both the scientific and patent literature. Specifically, we determined the half\u2010maximal inhibitory concentration (IC\n                    <jats:sub>50<\/jats:sub>\n                    ) for each inhibitor against MBLs belonging to the NDM and IMP families. In addition, the binding affinities of the inhibitors for Zn\n                    <jats:sup>2+<\/jats:sup>\n                    , Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u00a0and Mg\n                    <jats:sup>2+\u00a0<\/jats:sup>\n                    were assessed by using isothermal titration calorimetry (ITC). We also compared the ability of the different inhibitors to resensitize a highly resistant MBL\u2010expressing\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    strain to meropenem. These investigations reveal clear differences between the MBL inhibitors studied in terms of their IC\n                    <jats:sub>50<\/jats:sub>\n                    value, metal binding ability, and capacity to synergize with meropenem. Notably, our studies demonstrate that potent MBL inhibition and synergy with meropenem are not explicitly dependent on the capacity of an inhibitor to strongly chelate zinc.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202100042","type":"journal-article","created":{"date-parts":[[2021,2,5]],"date-time":"2021-02-05T21:25:19Z","timestamp":1612560319000},"page":"1651-1659","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Mechanistic Investigations of Metallo\u2010\u03b2\u2010lactamase Inhibitors: Strong Zinc Binding Is Not Required for Potent Enzyme Inhibition**"],"prefix":"10.1002","volume":"16","author":[{"given":"Nicola","family":"Wade","sequence":"first","affiliation":[{"name":"Biological Chemistry Group Institute of Biology Leiden Leiden University  Sylviusweg 72 2333 BE Leiden (The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamaleddin H. M. E.","family":"Tehrani","sequence":"additional","affiliation":[{"name":"Biological Chemistry Group Institute of Biology Leiden Leiden University  Sylviusweg 72 2333 BE Leiden (The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora C.","family":"Br\u00fcchle","sequence":"additional","affiliation":[{"name":"Biological Chemistry Group Institute of Biology Leiden Leiden University  Sylviusweg 72 2333 BE Leiden (The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthijs J.","family":"van Haren","sequence":"additional","affiliation":[{"name":"Biological Chemistry Group Institute of Biology Leiden Leiden University  Sylviusweg 72 2333 BE Leiden (The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vida","family":"Mashayekhi","sequence":"additional","affiliation":[{"name":"Department of Biology Utrecht University  Padualaan 8 3584 CH Utrecht (The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8246-3006","authenticated-orcid":false,"given":"Nathaniel I.","family":"Martin","sequence":"additional","affiliation":[{"name":"Biological Chemistry Group Institute of Biology Leiden Leiden University  Sylviusweg 72 2333 BE Leiden (The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,3,3]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(14)70780-7"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00037-09"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.1980.0049"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics7030061"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja508388e"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1107\/S1744309111029654"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi992569m"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-184036"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00774-09"},{"key":"e_1_2_7_10_1","first-page":"1","volume":"8","author":"Li T.","year":"2013","journal-title":"PLoS One"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.4.902"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2018.03.007"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature13445"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja303579d"},{"key":"e_1_2_7_15_1","doi-asserted-by":"crossref","unstructured":"A.\u2005J. 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