{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T00:31:22Z","timestamp":1793838682148,"version":"4.6.1"},"reference-count":40,"publisher":"American Chemical Society (ACS)","issue":"5","license":[{"start":{"date-parts":[[2020,4,16]],"date-time":"2020-04-16T00:00:00Z","timestamp":1586995200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2020,4,16]],"date-time":"2020-04-16T00:00:00Z","timestamp":1586995200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2020,4,16]],"date-time":"2020-04-16T00:00:00Z","timestamp":1586995200000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000082","name":"Division of Graduate Education","doi-asserted-by":"publisher","award":["DGE 1644868"],"award-info":[{"award-number":["DGE 1644868"]}],"id":[{"id":"10.13039\/100000082","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM084176"],"award-info":[{"award-number":["GM084176"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006510","name":"Duke University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006510","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,5,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Antibacterial drug resistance is a rapidly growing clinical threat, partially due to expression of \u03b2-lactamase enzymes, which confer resistance to bacteria by hydrolyzing and inactivating \u03b2-lactam antibiotics. The increasing prevalence of metallo-\u03b2-lactamases poses a unique challenge, as currently available \u03b2-lactamase inhibitors target the active site of serine \u03b2-lactamases but are ineffective against the zinc-containing active sites of metallo-\u03b2-lactamases. There is an urgent need for metallo-\u03b2-lactamase inhibitors and antibiotics that circumvent resistance mediated by metallo-\u03b2-lactamases in order to extend the utility of existing \u03b2-lactam antibiotics for treating infection. Here we investigated the antibacterial chelator-releasing prodrug PcephPT (2-((((6R,7R)-2-carboxy-8-oxo-7-(2-phenylacetamido)-5-thia-1-azabicyclo\u00ad[4.2.0]\u00adoct-2-en-3-yl)\u00admethyl)\u00adthio) pyridine 1-oxide) as an inhibitor of New Delhi metallo-\u03b2-lactamase 1 (NDM-1). PcephPT is an experimental compound that we have previously shown inhibits growth of \u03b2-lactamase-expressing E. coli using a mechanism that is dependent on both copper availability and \u03b2-lactamase expression. Here, we found that PcephPT, in addition to being a copper-dependent antibacterial compound, inhibits hydrolysis activity of purified NDM-1with an IC50 of 7.6 \u03bcM without removing zinc from the active site and restores activity of the carbapenem antibiotic meropenem against NDM-1-producing E. coli. This work demonstrates that targeting a metal-binding pharmacophore to \u03b2-lactamase-producing bacteria is a promising strategy for inhibition of both bacterial growth and metallo-\u03b2-lactamases.<\/jats:p>","DOI":"10.1021\/acsinfecdis.0c00083","type":"journal-article","created":{"date-parts":[[2020,4,16]],"date-time":"2020-04-16T16:49:57Z","timestamp":1587055797000},"page":"1264-1272","source":"Crossref","is-referenced-by-count":34,"title":["A Cephalosporin Prochelator Inhibits New Delhi Metallo-\u03b2-lactamase\n1 without Removing Zinc"],"prefix":"10.1021","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2113-3449","authenticated-orcid":true,"given":"Abigail\nC.","family":"Jackson","sequence":"first","affiliation":[{"name":"Duke University , , 124 Science Drive , , ,","place":["Durham, North Carolina, United States, 27708"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline M.","family":"Zaengle-Barone","sequence":"additional","affiliation":[{"name":"Duke University , , 124 Science Drive , , ,","place":["Durham, North Carolina, United States, 27708"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena A.","family":"Puccio","sequence":"additional","affiliation":[{"name":"Duke University , , 124 Science Drive , , ,","place":["Durham, North Carolina, United States, 27708"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9015-0998","authenticated-orcid":true,"given":"Katherine J.","family":"Franz","sequence":"additional","affiliation":[{"name":"Duke University , , 124 Science Drive , , ,","place":["Durham, North Carolina, United States, 27708"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,4,16]]},"reference":[{"key":"2026081806113701800_cit1","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1021\/cr030102i","article-title":"Bacterial Resistance to \u03b2-Lactam\nAntibiotics: Compelling Opportunism, Compelling Opportunity","volume":"105","author":"Fisher","year":"2005","journal-title":"Chem. Rev."},{"key":"2026081806113701800_cit2","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1021\/ar0400241","article-title":"Metallo-\u03b2-lactamases: Novel\nWeaponry for Antibiotic Resistance in Bacteria","volume":"39","author":"Crowder","year":"2006","journal-title":"Acc. Chem. Res."},{"key":"2026081806113701800_cit3","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1111\/j.1749-6632.2012.06796.x","article-title":"Metallo-\u03b2-lactamase\nstructure and function","volume":"1277","author":"Palzkill","year":"2013","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"2026081806113701800_cit4","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1016\/j.tim.2011.09.005","article-title":"The emerging\nNDM carbapenemases","volume":"19","author":"Nordmann","year":"2011","journal-title":"Trends Microbiol."},{"key":"2026081806113701800_cit5","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1021\/acsinfecdis.8b00037","article-title":"Copper\nInfluences the Antibacterial\nOutcomes of a \u03b2-Lactamase-Activated Prochelator against Drug-Resistant\nBacteria","volume":"4","author":"Zaengle-Barone","year":"2018","journal-title":"ACS Infect. Dis."},{"key":"2026081806113701800_cit6","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1128\/AAC.10.2.245","article-title":"A New Cephalosporin with a Dual Mode\nof Action","volume":"10","author":"O\u2019Callaghan","year":"1976","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026081806113701800_cit7","doi-asserted-by":"publisher","first-page":"5699","DOI":"10.1016\/S0040-4020(00)00419-1","article-title":"\u03b2-Lactamase-Dependent\nProdrugs\ue5f8Recent Developments","volume":"56","author":"Smyth","year":"2000","journal-title":"Tetrahedron"},{"key":"2026081806113701800_cit8","doi-asserted-by":"publisher","first-page":"6645","DOI":"10.1021\/acs.jmedchem.6b00485","article-title":"Development of a\nDual-Acting Antibacterial Agent (TNP-2092)\nfor the Treatment of Persistent Bacterial Infections","volume":"59","author":"Ma","year":"2016","journal-title":"J. Med. Chem."},{"key":"2026081806113701800_cit9","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1021\/acs.joc.6b02272","article-title":"Alternate\n\u201cDrug\u201d\nDelivery Utilizing \u03b2-Lactam Cores: Syntheses and Biological\nEvaluation of \u03b2-Lactams Bearing Isocyanate Precursors","volume":"82","author":"Majewski","year":"2017","journal-title":"J. Org. Chem."},{"key":"2026081806113701800_cit10","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1016\/j.bmcl.2008.12.057","article-title":"Design and synthesis of a \u03b2-lactamase\nactivated 5-fluorouracil prodrug","volume":"19","author":"Phelan","year":"2009","journal-title":"Bioorg. Med.\nChem. Lett."},{"key":"2026081806113701800_cit11","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1038\/nchem.1435","article-title":"Rapid point-of-care\ndetection of the tuberculosis pathogen using a BlaC-specific fluorogenic\nprobe","volume":"4","author":"Xie","year":"2012","journal-title":"Nat. Chem."},{"key":"2026081806113701800_cit12","doi-asserted-by":"publisher","first-page":"3845","DOI":"10.1021\/acs.jmedchem.8b00218","article-title":"A Synthetic Dual\nDrug Sideromycin Induces Gram-Negative\nBacteria To Commit Suicide with a Gram-Positive Antibiotic","volume":"61","author":"Liu","year":"2018","journal-title":"J. Med. Chem."},{"key":"2026081806113701800_cit13","doi-asserted-by":"publisher","first-page":"5753","DOI":"10.1128\/AAC.00724-11","article-title":"Zinc Pyrithione Inhibits Yeast Growth through Copper\nInflux and Inactivation of Iron-Sulfur Proteins","volume":"55","author":"Reeder","year":"2011","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026081806113701800_cit14","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1111\/j.1365-2133.2011.10571.x","article-title":"The antifungal mechanism of action of zinc pyrithione","volume":"165","author":"Reeder","year":"2011","journal-title":"Br. J. Dermatol."},{"key":"2026081806113701800_cit15","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1016\/j.jbiosc.2009.10.025","article-title":"DNA microarray\nanalysis suggests\nthat zinc pyrithione causes iron starvation to the yeast Saccharomyces\ncerevisiae","volume":"109","author":"Yasokawa","year":"2010","journal-title":"J. Biosci. Bioeng."},{"key":"2026081806113701800_cit16","doi-asserted-by":"publisher","first-page":"12086","DOI":"10.1038\/s41598-018-30588-2","article-title":"Understanding the\nMechanism of Action of the Anti-Dandruff Agent Zinc Pyrithione against\nMalassezia restricta","volume":"8","author":"Park","year":"2018","journal-title":"Sci. Rep."},{"key":"2026081806113701800_cit17","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1111\/1574-6976.12087","article-title":"Metal limitation\nand toxicity at the interface between\nhost and pathogen","volume":"38","author":"Becker","year":"2014","journal-title":"FEMS Microbiol Rev."},{"key":"2026081806113701800_cit18","doi-asserted-by":"publisher","first-page":"18954","DOI":"10.1074\/jbc.R115.647099","article-title":"The Role of Copper\nand Zinc Toxicity in Innate Immune Defense against Bacterial Pathogens","volume":"290","author":"Djoko","year":"2015","journal-title":"J. Biol. Chem."},{"key":"2026081806113701800_cit19","doi-asserted-by":"publisher","first-page":"13549","DOI":"10.1074\/jbc.R111.316406","article-title":"Copper Homeostasis at the Host-Pathogen Interface","volume":"287","author":"Hodgkinson","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2026081806113701800_cit20","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1021\/acsinfecdis.9b00112","article-title":"Dual-Pharmacophore\nPyrithione-Containing Cephalosporins Kill Both Replicating and Nonreplicating\nMycobacterium tuberculosis","volume":"5","author":"Lopez\nQuezada","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"2026081806113701800_cit21","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1016\/j.tips.2018.03.007","article-title":"The Continuing\nChallenge of Metallo-\u03b2-Lactamase Inhibition: Mechanism Matters","volume":"39","author":"Ju","year":"2018","journal-title":"Trends Pharmacol. Sci."},{"key":"2026081806113701800_cit22","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1007\/s00775-018-1593-1","article-title":"Isosteres\nof hydroxypyridinethione\nas drug-like pharmacophores for metalloenzyme inhibition","volume":"23","author":"Adamek","year":"2018","journal-title":"JBIC, J. Biol. Inorg. Chem."},{"key":"2026081806113701800_cit23","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02280-17","article-title":"Copper ions and\ncoordination complexes as novel carbapenem\nadjuvants","volume":"62","author":"Djoko","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026081806113701800_cit24","doi-asserted-by":"publisher","first-page":"4524","DOI":"10.1038\/s41467-018-06839-1","article-title":"Differential active\nsite requirements for NDM-1 \u03b2-lactamase hydrolysis of carbapenem\nversus penicillin and cephalosporin antibiotics","volume":"9","author":"Sun","year":"2018","journal-title":"Nat. Commun."},{"key":"2026081806113701800_cit25","doi-asserted-by":"publisher","first-page":"5046","DOI":"10.1128\/AAC.00774-09","article-title":"Characterization\nof a New Metallo-\u03b2-Lactamase\nGene, blaNDM\u20111, and a Novel Erythromycin Esterase\nGene Carried on a Unique Genetic Structure in Klebsiella pneumoniae Sequence Type 14 from India","volume":"53","author":"Yong","year":"2009","journal-title":"Antimicrob. Agents\nChemother."},{"key":"2026081806113701800_cit26","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/S1473-3099(11)70059-7","article-title":"Dissemination of\nNDM-1 positive bacteria in the New Delhi environment and its implications\nfor human health: an environmental point prevalence study","volume":"11","author":"Walsh","year":"2011","journal-title":"Lancet Infect. Dis."},{"key":"2026081806113701800_cit27","doi-asserted-by":"publisher","first-page":"2717","DOI":"10.1073\/pnas.1612810114","article-title":"Role for dithiolopyrrolones in disrupting\nbacterial metal homeostasis","volume":"114","author":"Chan","year":"2017","journal-title":"Proc. Natl. Acad.\nSci. U. S. A."},{"key":"2026081806113701800_cit28","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1021\/acsinfecdis.9b00052","article-title":"Active-site druggability of carbapenemases and broad-spectrum inhibitor\ndiscovery","volume":"5","author":"Torelli","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"2026081806113701800_cit29","doi-asserted-by":"publisher","first-page":"8544","DOI":"10.1021\/acs.jmedchem.9b00911","article-title":"Bicyclic Boronate VNRX-5133 Inhibits\nMetallo- and Serine-\u03b2-Lactamases","volume":"62","author":"Krajnc","year":"2019","journal-title":"J. Med.\nChem."},{"key":"2026081806113701800_cit30","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1021\/acsinfecdis.8b00366","article-title":"Novel Mercapto\nPropionamide Derivatives with Potent New Delhi Metallo-\u03b2-Lactamase-1\n(NDM-1) Inhibitory Activity and Low Toxicity","volume":"5","author":"Meng","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"2026081806113701800_cit31","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1021\/acsinfecdis.8b00246","article-title":"SAR studies\nleading\nto the identification of a novel series of metallo-\u03b2-lactamase\ninhibitors for the treatment of carbapenem-resistant Enterobacteriaceae\ninfections that display efficacy in an animal infection model","volume":"5","author":"Leiris","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"2026081806113701800_cit32","doi-asserted-by":"publisher","first-page":"1407","DOI":"10.1021\/acsinfecdis.8b00137","article-title":"Synthesis\nand preclinical evaluation of TPA-based zinc chelators as metallo-\u03b2-lactamase\ninhibitors","volume":"4","author":"Schnaars","year":"2018","journal-title":"ACS Infect. Dis."},{"key":"2026081806113701800_cit33","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00074-18","article-title":"Discovery of a Novel Metallo-\u03b2-Lactamase\nInhibitor That Potentiates Meropenem Activity against Carbapenem-Resistant\nEnterobacteriaceae","volume":"62","author":"Everett","year":"2018","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026081806113701800_cit34","doi-asserted-by":"publisher","first-page":"7267","DOI":"10.1021\/acs.jmedchem.7b00407","article-title":"Dipicolinic\nAcid Derivatives as Inhibitors of New Delhi Metallo-\u03b2-lactamase-1","volume":"60","author":"Chen","year":"2017","journal-title":"J. Med. Chem."},{"key":"2026081806113701800_cit35","doi-asserted-by":"publisher","first-page":"864","DOI":"10.1086\/381972","article-title":"Clinical Relevance of Bacteriostatic\nversus Bactericidal\nMechanisms of Action in the Treatment of Gram-Positive Bacterial Infections","volume":"38","author":"Pankey","year":"2004","journal-title":"Clin. Infect. Dis."},{"key":"2026081806113701800_cit36","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01849-17","article-title":"Clinical Evolution of New Delhi Metallo-\u03b2-Lactamase\n(NDM) Optimizes Resistance under Zn\u00ad(II) Deprivation","volume":"62","author":"Bahr","year":"2017","journal-title":"Antimicrob. Agents Chemother."},{"key":"2026081806113701800_cit37","doi-asserted-by":"publisher","first-page":"10102","DOI":"10.1021\/bi201449r","article-title":"Characterization of\nPurified New Delhi Metallo-\u03b2-lactamase-1","volume":"50","author":"Thomas","year":"2011","journal-title":"Biochemistry"},{"key":"2026081806113701800_cit38","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1002\/cmdc.201900172","article-title":"Investigation of\nDipicolinic Acid Isosteres for the Inhibition of Metallo-beta-Lactamases","volume":"14","author":"Chen","year":"2019","journal-title":"ChemMedChem"},{"key":"2026081806113701800_cit39","doi-asserted-by":"publisher","first-page":"7273","DOI":"10.1021\/ja410376s","article-title":"Spectroscopic and Mechanistic Studies\nof Heterodimetallic Forms of Metallo-\u03b2-lactamase NDM-1","volume":"136","author":"Yang","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"2026081806113701800_cit40","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1021\/acsinfecdis.7b00106","article-title":"Probing the Interaction of Aspergillomarasmine A with\nMetallo-\u03b2-lactamases NDM-1, VIM-2, and IMP-7","volume":"4","author":"Bergstrom","year":"2018","journal-title":"ACS Infect. Dis."}],"container-title":["ACS Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsinfecdis.0c00083","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/6\/5\/1264\/12721106\/id0c00083.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article-pdf\/6\/5\/1264\/12721106\/id0c00083.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T10:55:23Z","timestamp":1787050523000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/aidcbc\/article\/6\/5\/1264\/1292455\/A-Cephalosporin-Prochelator-Inhibits-New-Delhi"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,16]]},"references-count":40,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,4,16]]},"published-print":{"date-parts":[[2020,5,8]]}},"URL":"https:\/\/doi.org\/10.1021\/acsinfecdis.0c00083","relation":{},"ISSN":["2373-8227"],"issn-type":[{"value":"2373-8227","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,16]]}}}