α-Aminophosphonate inhibitors of metallo-β-lactamases NDM-1 and VIM-2
Palica, 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. RSC Medicinal Chemistry, 14, 2277-2300. https://doi.org/10.1039/d3md00286a
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RSC Medicinal ChemistryAuthors
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2023Copyright
© 2023 The Royal Society of Chemistry
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 (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.
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Royal Society of Chemistry (RSC)ISSN Search the Publication Forum
2632-8682Publication in research information system
https://converis.jyu.fi/converis/portal/detail/Publication/194183666
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Research Council of FinlandFunding program(s)
Research costs of Academy Research Fellow, AoFAdditional information about funding
We 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. ...License
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