α-Aminophosphonate inhibitors of metallo-β-lactamases NDM-1 and VIM-2.

Autor: Palica K; Department of Chemistry - BMC, Organic Chemistry, Uppsala University Husargatan 3 752 37 Uppsala Sweden hanna.andersson@redglead.com mate.erdelyi@kemi.uu.se., Deufel F; Department of Chemistry - BMC, Organic Chemistry, Uppsala University Husargatan 3 752 37 Uppsala Sweden hanna.andersson@redglead.com mate.erdelyi@kemi.uu.se., Skagseth S; Department of Chemistry, Faculty of Science and Technology, UiT The Arctic University of Norway N-9037 Tromsø Norway., Di Santo Metzler GP; Department of Chemistry & Molecular Biology, University of Gothenburg Medicinaregatan 9C 413 90 Göteborg Sweden.; Center for Antibiotics Resistance Research (CARe) at University of Gothenburg 413 90 Göteborg Sweden., Thoma J; Department of Chemistry & Molecular Biology, University of Gothenburg Medicinaregatan 9C 413 90 Göteborg Sweden.; Center for Antibiotics Resistance Research (CARe) at University of Gothenburg 413 90 Göteborg Sweden., Andersson Rasmussen A; Department of Chemistry - BMC, Organic Chemistry, Uppsala University Husargatan 3 752 37 Uppsala Sweden hanna.andersson@redglead.com mate.erdelyi@kemi.uu.se., Valkonen A; Department of Chemistry, University of Jyvaskyla Survontie 9B 40014 Finland., Sunnerhagen P; Department of Chemistry & Molecular Biology, University of Gothenburg Medicinaregatan 9C 413 90 Göteborg Sweden., Leiros HS; Department of Chemistry, Faculty of Science and Technology, UiT The Arctic University of Norway N-9037 Tromsø Norway., Andersson H; Department of Chemistry - BMC, Organic Chemistry, Uppsala University Husargatan 3 752 37 Uppsala Sweden hanna.andersson@redglead.com mate.erdelyi@kemi.uu.se., Erdelyi M; Department of Chemistry - BMC, Organic Chemistry, Uppsala University Husargatan 3 752 37 Uppsala Sweden hanna.andersson@redglead.com mate.erdelyi@kemi.uu.se.
Jazyk: angličtina
Zdroj: RSC medicinal chemistry [RSC Med Chem] 2023 Aug 02; Vol. 14 (11), pp. 2277-2300. Date of Electronic Publication: 2023 Aug 02 (Print Publication: 2023).
DOI: 10.1039/d3md00286a
Abstrakt: The 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 (IC 50 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.
Competing Interests: There are no conflicts to declare.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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