A structural and mechanistic view on enzymes evolution
Publications
2025
Hovd Rebekka, R. et al. APC24-7, a covalent combination of boronic acid and chelator moieties, restores β-lactam efficiency against metallo-β-lactamase-producers. mSphere 0, e00418-00425 (2025). https://doi.org:10.1128/msphere.00418-25
Sakuma, M., Buda, K., Bunzel, H. A., Frøhlich, C. & Tokuriki, N. Functional sub-states link conformational landscapes and protein evolution. Current Opinion in Structural Biology 94, 103134 (2025). https://doi.org:https://doi.org/10.1016/j.sbi.2025.103134
Gulyás, K.V., Zhou, L., Salamonsen, D. et al. Dynamically chiral phosphonic acid-type metallo-β-lactamase inhibitors. Commun Chem 8, 119 (2025). https://doi.org/10.1038/s42004-025-01510-5
Lorentzen, Ø. M., Abel, S., Johnsen, P. J. & Frøhlich, C. Biofilm selection constitutively activates c-di-GMP synthesis by the bifunctional enzyme MbaA. bioRxiv, 2025.2002.2013.638143 (2025). https://doi.org:10.1101/2025.02.13.638143
2024
Lorentzen, Ø. M., Haukefer, A. S. B., Johnsen, P. J. & Frøhlich, C. The Biofilm Lifestyle Shapes the Evolution of β-Lactamases. Genome Biology and Evolution, evae030 (2024). https://doi.org:10.1093/gbe/evae030
Fröhlich, C. et al. Epistasis arises from shifting the rate-limiting step during enzyme evolution of a β-lactamase. Nature Catalysis (2024). https://doi.org:10.1038/s41929-024-01117-4
Kondratieva, A. et al. Fluorinated captopril analogues inhibit metallo-beta-lactamases and facilitate structure determination of NDM-1 binding pose. Eur J Med Chem 266, 116140 (2024). https://doi.org:10.1016/j.ejmech.2024.116140
2023
Jia, Y., Schröder, B., Pfeifer, Y., Fröhlich, C., Deng, L., Arkona, C., Kuropka, B., Sticht, J., Ataka, K., Bergemann, S., Wolber, G., Nitsche, C., Mielke, M., Leiros, H.-K. S., Werner, G. & Rademann, J. (2023) Kinetics, thermodynamics, and structural effects of quinoline-2-carboxylates, zinc-binding inhibitors of New Delhi metallo-β-lactamase-1 (NDM 1) re-sensitizing multi-drug resistant bacteria for carbapenems, J Med Chem. 66 (17), 11761-11791. doi.org/10.1021/acs.jmedchem.3c00171
Palica, K., Deufel, F., Skagseth, S., Santo Metzler, G. P. D., Thoma, J., Rasmussen, A. A., Valkonen, A., Sunnerhagen, P., Leiros, H.-K. S., Andersson, H. & Erdélyi, M. (2023) α-Aminophosphonate inhibitors of metallo-β-lactamases NDM-1 and VIM-2, RSC Medicinal Chemistry. doi.org/10.1039/D3MD00286A
2022
Fröhlich C., Sørum, V., Tokuriki, N., Johnsen P.J. & Samuelsen Ø. (2022) Evolution of β-lactamase-mediated cefiderocol resistance. J. Antimicrob. Chemother. 77(9):2429-2436. doi: 10.1093/jac/dkac221
Palica, K., Vorácová, M., Skagseth, S., Rasmussen, A.R., Allander, L., Hubert, M.,Sandegren, L., Leiros, H.-K.S., Andersson, H. & Erdélyi, M. (2022) Metallo-β-lactamase inhibitor phosphonamidate monoesters. 2022 ACS Omega, 25;7(5):4550-4562. doi: 10.1021/acsomega.1c06527
2021
Lund, B.A., Thomassen, A.M., Carlsen, T.J.W & Leiros, H.-K.S.* (2021) Biochemical and biophysical characterization of the OXA-48-like carbapenemase OXA-436. Acta Crystallogr F Struct Biol Commun. 77 (9), 312-318. doi: 10.1107/S2053230X21008645.
Fröhlich C., Gama J.A., Harms K., Hirvonen V.H.A., Lund B.A., van der Kamp M.W., Johnsen P.J., Samuelsen Ø. and Leiros H.-K.S.* (2021) Cryptic β-lactamase evolution is driven by low β-lactam concentrations. bioRxiv, 2020.2012.2001.404343. First published on, doi: 10.1101/2020.12.01.404343. mSphere. 6(2):e00108-21. doi: 10.1128/mSphere.00108-21.
Fröhlich, C., Chen, J. Z., Gholipour, S., Erdogan, A. N. & Tokuriki, N. Evolution of β-lactamases and enzyme promiscuity. Protein Eng Des Sel 34(2021). https://doi.org:10.1093/protein/gzab013
2020
Leiros, H.-K.S.* Thomassen, A. M., Samuelsen, Ø., Flach, C.-F., Kotsakis, S. D. & Larsson, D. G. J. (2020) Structural insights into the enhanced carbapenemase efficiency of OXA-655 compared to OXA-10. Febs Open Bio, 10(9):1821-1832. doi: 10.1002/2211-5463.12935.
Muhammad, Z. et al. Structural studies of triazole inhibitors with promising inhibitor effects against antibiotic resistance metallo-beta-lactamases. Bioorg Med Chem 28, 115598 (2020). https://doi.org:10.1016/j.bmc.2020.115598
Fröhlich, C. et al. Structural and biochemical characterization of the environmental MBLs MYO-1, ECV-1 and SHD-1. J Antimicrob Chemother 75, 2554-2563 (2020). https://doi.org:10.1093/jac/dkaa175
Samuelsen, O. et al. ZN148 Is a Modular Synthetic Metallo-β-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo. Antimicrob Agents Chemother 64 (2020). https://doi.org:10.1128/AAC.02415-19
2019
Fröhlich, C. et al. OXA-48-Mediated Ceftazidime-Avibactam Resistance Is Associated with Evolutionary Trade-Offs. mSphere 4, e00024-00019 (2019). https://doi.org:10.1128/mSphere.00024-19
Fröhlich, C. et al. Structural and biochemical characterization of the environmental MBLs MYO-1, ECV-1 and SHD-1. J Antimicrob Chemother 75, 2554-2563 (2020). https://doi.org:10.1093/jac/dkaa175
Prandina, A. et al. Synthesis and biological evaluation of new dipicolylamine zinc chelators as metallo-β-lactamase inhibitors. Tetrahedron 75, 1525-1540 (2019). https://doi.org:https://doi.org/10.1016/j.tet.2019.02.004
Kildahl-Andersen, G. et al. Synthesis and biological evaluation of zinc chelating compounds as metallo-beta-lactamase inhibitors. Medchemcomm10, 528-537 (2019). https://doi.org:10.1039/c8md00578h
2018
Lund, B. A., Thomassen, A. M., Nesheim, B. H. B., Carlsen, T. J., Isaksson, J., Christopeit, T., and Leiros, H.-K. S.* (2018) The biological assembly of OXA-48 reveal a dimer interface high charge complementarity and very high affinity, FEBS J. 285 (22), 4214-4228 doi:10.1111/febs.14643.
Akhter. S., Lund, B. A., Isamel, A., Lange, M., Isaksson, J., Christopeit, T., Leiros, H.-K. S.* & Bayer, A. (2018) A focused fragment library targeting the antibiotic resistance enzyme - Oxacillinase-48: Synthesis, structural evaluation and inhibitor design., Eur J Med Chem. 145, 634-648. DOI: 10.1016/j.ejmech.2017.12.085
Marcoccia, F., Leiros, H.-K. S., Aschi, M., Amicosante, G. & Perilli, M. (2018) Exploring the role of L209 residue in the active site of NDM-1 a metallo-β-lactamase, PLOS One. 13 (1), e0189686. DOI: 10.1371/journal.pone.0189686.
Schnaars, C. et al. Synthesis and Preclinical Evaluation of TPA-Based Zinc Chelators as Metallo-β-lactamase Inhibitors. ACS Infect Dis 4, 1407-1422 (2018). https://doi.org:10.1021/acsinfecdis.8b00137
2017
Samuelsen, Ø., Hansen, F., Aasnæs, B., Hasman, H., Lund, B.A., Leiros, H.K.S.,Lilje, B., Janice, J., Jakobsen, L., Littauer, P., Søes, L.M., Holzknecht, B.J., Andersen, L.P., Stegger, M., Andersen, P.S., Hammerum, A.M. (2017). Dissemination and Characteristics of a Novel Plasmid-Encoded Carbapenem-Hydrolyzing Class D β-Lactamase, OXA-436 from Four Patients Involving Six Different Hospitals in Denmark. Antimicrob Agents Chemother. 62 (1) pii: e01260-17. doi: 10.1128/AAC.01260-17.
Lund, B.A., Thomassen, A.M., Carlsen, T.J.O., Leiros, H.-K.S.* (2017) Structure, activity and thermostability investigations of OXA-163, OXA-181 and OXA-245 using biochemical analysis, crystal structures and differential scanning calorimetry analysis. Acta Crystallogr F Struct Biol Commun. 73(Pt 10), 579-587. doi.org/10.1107/S2053230X17013838
Skagseth, S., Christopeit, T., Akhter, S., Bayer, A., Samuelsen, Ø. & Leiros, H.-K. S.*(2017) Structural insights into TMB-1 and the role of residue 119 and 228 in substrate and inhibitor binding, Antimicrobial Agents and Chemotherapy. 61 (8), e02602-16. doi.org/10.1128/AAC.02602-16.
Skagseth, S., Akhter, S., Paulsen, M.H., Muhammad, Z., Lauksund, S., Samuelsen, Ø., Leiros, H.-K. S.* & Bayer, A.*(2017) Metallo-β-lactamase inhibitors by bioisosteric replacement: preparation, activity and binding, European Journal of Medicinal Chemistry. 138, 159-173. doi.org/10.1016/j.ejmech.2017.04.035.
2016
Christopeit, T., Yang, K.-W., Yang, S.-K. & Leiros, H.-K. S.*(2016) The structure of the metallo-β-lactamase VIM-2 in complex with a triazolylthioacetamide inhibitor, Acta Crystallogr F Struct Biol Commun, 72, 813-819. DOI: 10.1107/S2053230X16016113.
Lund, B.A., Christopeit, T., Guttormsen, Y., Bayer, A.,Leiros, H.-K.S.* (2016). Surface plasmon resonance based screening and design of inhibitor scaffolds for the antibiotic resistance enzyme OXA-48. J. Med. Chem.: 59, 5542–5554. Doi.org/10.1021/acs.jmedchem.6b00660.
Christopeit, T., Albert, A., Leiros, H.-K.S.(2016) Discovery of a novel covalent non-ß-lactam inhibitor of the metallo-ß-lactamase NDM-1, Bioorg. Med. Chem., 24: 2947-53. DOI.org/10.1016/j.bmc.2016.04.064
Christopeit, T.,Leiros, H.-K.S. (2016). Fragment-based Discovery of Inhibitor Scaffolds Targeting the Metallo-ß-lactamases NDM-1 and VIM-2. Bioorg. Med. Chem. Lett. 8:1973-1977. DOI.org/10.1016/j.bmcl.2016.03.004
2015
Skagseth, S., Carlsen, T.J., Bjerga, G.E., Spencer, J., Samuelsen, Ø.,Leiros, H.-K.S. * (2015). Investigating the role of residues W228 and Y233 in the structure and activity of the GIM-1 metallo-ß-lactamase. Role of Residues W228 and Y233 in the Structure and Activity of Metallo-ß-Lactamase GIM-1. Antimicrob. Agents. Chemother. 60, 990-1002. DOI.org/10.1128/aac.02017-15.
Christopeit T., Carlsen, T.J., Helland, R.,Leiros H.-K.S.* (2015). Discovery of Novel Inhibitor Scaffolds against the Metallo-ß-lactamase VIM-2 by Surface Plasmon Resonance (SPR) Based Fragment Screening. J. Med. Chem. 58: 8671-8682. DOI.org/10.1021/acs.jmedchem.5b01289
Leiros, H.-K. S.,Edvardsen, K. S., Bjerga, G. E. K. & Samuelsen, Ø. (2015). Structural and biochemical characterization of VIM-26 show that Leu224 has implications for the substrate specificity of VIM metallo-ß-lactamases. The FEBS journal, 282(6), 1031-1042. DOI.org/10.1111/febs.13200
2014
Leiros, H.-K. S., Skagseth, S., Edvardsen, K. S. W., Lorentzen, M. S., Bjerga, G. E. K., Leiros, I. & Samuelsen, Ø. (2014) His224 Alters the R2 Drug Binding Site and Phe218 Influences the Catalytic Efficiency of the Metallo-ß-Lactamase VIM-7. Antimicrob. Agents Chemother. 58, 4826-36. DOI.org/10.1128/AAC.02735-13.
Lund, B.A., Leiros, H.-K.S.& Bjerga, G.E.K. (2014) A high-throughput, restriction-free cloning strategy based on ccdB-gene replacement. Microbial Cell Factories. 13 (1), 38. DOI.org/10.1186/1475-2859-13-38
2013
Borra, P. S. Samuelsen, Ø Spencer, J. Walsh, T. R., Lorentzen, M.S. & Leiros, H-K.S.*(2013) Crystal structures of Pseudomonas aeruginosa GIM-1: Active site plasticity in metallo-ß-lactamases Antimicrob Agents Chemother. 57, 848-54. DOI: 10.1128/AAC.02227-12
2012/2011
Leiros, H-K.S., Borrai, P.S., Brandsdal, B.O., Edvardsen, K.S., Spencer, J., Walsh, T.R. & Samuelsen Ø. (2012) Crystal structure of the mobile metallo-ß-lactamase AIM-1 from Pseudomonas aeruginosa: insights into antibiotic binding and the role of Gln157. Antimicrob. Agents Chemother. 56, 4341-4353. DOI: 10.1128/AAC.00448-12
Borra, P.S., Leiros, H.-K.S.,Ahmad, R., Spencer, J., Leiros, I., Walsh, T.R., Sundsfjord, A. & Samuelsen Ø. (2011) Structural and computational investigations of VIM-7: Insights into the substrate specificity of VIM metallo-ß-lactamases. J. Mol. Biol., 411 (1), 174-189. DOI: 10.1016/j.jmb.2011.05.035