Näytä suppeat kuvailutiedot

dc.contributor.authorPalica, Katarzyna
dc.contributor.authorDeufel, Fritz
dc.contributor.authorSkagseth, Susann
dc.contributor.authorDi Santo Metzler, Gabriela Paula
dc.contributor.authorThoma, Johannes
dc.contributor.authorAndersson Rasmussen, Anna
dc.contributor.authorValkonen, Arto
dc.contributor.authorSunnerhagen, Per
dc.contributor.authorLeiros, Hanna-Kirsti S.
dc.contributor.authorAndersson, Hanna
dc.contributor.authorErdelyi, Mate
dc.date.accessioned2023-10-26T09:58:15Z
dc.date.available2023-10-26T09:58:15Z
dc.date.issued2023
dc.identifier.citationPalica, K., Deufel, F., Skagseth, S., Di Santo Metzler, G. P., Thoma, J., Andersson Rasmussen, A., Valkonen, A., Sunnerhagen, P., Leiros, H.-K. S., Andersson, H., & Erdelyi, M. (2023). α-Aminophosphonate inhibitors of metallo-β-lactamases NDM-1 and VIM-2. <i>RSC Medicinal Chemistry</i>, <i>14</i>, 2277-2300. <a href="https://doi.org/10.1039/d3md00286a" target="_blank">https://doi.org/10.1039/d3md00286a</a>
dc.identifier.otherCONVID_194183666
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/90724
dc.description.abstractThe upswing of antibiotic resistance is an escalating threat to human health. Resistance mediated by bacterial metallo-β-lactamases is of particular concern as these enzymes degrade β-lactams, our most frequently prescribed class of antibiotics. Inhibition of metallo-β-lactamases could allow the continued use of existing β-lactam antibiotics, such as penicillins, cephalosporins and carbapenems, whose applicability is becoming ever more limited. The design, synthesis, and NDM-1, VIM-2, and GIM-1 inhibitory activities (IC50 4.1–506 μM) of a series of novel non-cytotoxic α-aminophosphonate-based inhibitor candidates are presented herein. We disclose the solution NMR spectroscopic and computational investigation of their NDM-1 and VIM-2 binding sites and binding modes. Whereas the binding modes of the inhibitors are similar, VIM-2 showed a somewhat higher conformational flexibility, and complexed a larger number of inhibitor candidates in more varying binding modes than NDM-1. Phosphonate-type inhibitors may be potential candidates for development into therapeutics to combat metallo-β-lactamase resistant bacteria.en
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherRoyal Society of Chemistry (RSC)
dc.relation.ispartofseriesRSC Medicinal Chemistry
dc.rightsCC BY 3.0
dc.titleα-Aminophosphonate inhibitors of metallo-β-lactamases NDM-1 and VIM-2
dc.typearticle
dc.identifier.urnURN:NBN:fi:jyu-202310266751
dc.contributor.laitosKemian laitosfi
dc.contributor.laitosDepartment of Chemistryen
dc.contributor.oppiaineOrgaaninen kemiafi
dc.contributor.oppiaineOrganic Chemistryen
dc.type.urihttp://purl.org/eprint/type/JournalArticle
dc.type.coarhttp://purl.org/coar/resource_type/c_2df8fbb1
dc.description.reviewstatuspeerReviewed
dc.format.pagerange2277-2300
dc.relation.issn2632-8682
dc.relation.volume14
dc.type.versionpublishedVersion
dc.rights.copyright© 2023 The Royal Society of Chemistry
dc.rights.accesslevelopenAccessfi
dc.relation.grantnumber335600
dc.relation.grantnumber314343
dc.subject.ysolääkekemia
dc.subject.ysoorgaaniset yhdisteet
dc.subject.ysoantibioottiresistenssi
dc.subject.ysolääkkeet
dc.subject.ysoantibiootit
dc.format.contentfulltext
jyx.subject.urihttp://www.yso.fi/onto/yso/p25557
jyx.subject.urihttp://www.yso.fi/onto/yso/p3841
jyx.subject.urihttp://www.yso.fi/onto/yso/p29640
jyx.subject.urihttp://www.yso.fi/onto/yso/p1077
jyx.subject.urihttp://www.yso.fi/onto/yso/p10820
dc.rights.urlhttps://creativecommons.org/licenses/by/3.0/
dc.relation.doi10.1039/d3md00286a
dc.relation.funderResearch Council of Finlanden
dc.relation.funderResearch Council of Finlanden
dc.relation.funderSuomen Akatemiafi
dc.relation.funderSuomen Akatemiafi
jyx.fundingprogramResearch costs of Academy Research Fellow, AoFen
jyx.fundingprogramResearch costs of Academy Research Fellow, AoFen
jyx.fundingprogramAkatemiatutkijan tutkimuskulut, SAfi
jyx.fundingprogramAkatemiatutkijan tutkimuskulut, SAfi
jyx.fundinginformationWe acknowledge the Swedish Research Council for financial support (2013-8804), Sven and Lilly Lawski Foundation, the Center for Antibiotics Resistance Research (CARe) at University of Gothenburg, Svenska Sällskapet för Medicinsk Forskning (PD20-0191), the Academy of Finland (grant no. 314343 and 335600) and the Åke Wiberg Foundation (M21-0225). The Lund Protein Production Platform (LP3) at Lund University, managed by Wolfgang Knecht, is acknowledged for NDM-1 and VIM-2 protein expression. This project made use of the NMR Uppsala infrastructure, which is funded by the Department of Chemistry – BMC and the Disciplinary Domain of Medicine and Pharmacy and had high-resolution mass spectra obtained by Stenhagen Analyslab AB. Part of the computations studies was performed on resources provided by Swedish National Infrastructure for Computing (SNIC) through National Supercomputer Center (NSC) under Project SNIC 2020/5-435. Crystallographic infrastructure in the Department of Chemistry at the University of Jyväskylä were successfully utilized.
dc.type.okmA1


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