Imitation of β-Lactam Binding Enables Broad-Spectrum Metallo-β-Lactamase Inhibitors
Nature Chemistry 2022
J Brem, T Panduwawala, J.U Hansen, J Hewitt, E Liepins, P Donets, L Espina, A.J.M Farley, K Shubin, G.G Campillos, P Kiuru, S Shishodia, D Krahn, R.K Lesniak, J Schmidt, K Calvopina, M-C Turrientes, M.E Kavanagh, D Lubriks, P Hinchliffe, G.W Langley, A.F Aboklaish, A Eneroth, M Backlund, A.G Baran, EI Nielsen, M Speake, J Kuka, J Robinson, S Grīnberga], L Robinson, M.A McDonough, A.M Rydzik, T.M Leissing, J.C Jimenez-Castellanos, M.B Avison, S Da Silva Pinto, A.D Pannifer, M Martjuga, E Widlake, M Priede, I Hopkins Navratilova, M Gniadkowski, A.K Belfrage, P Brandt, J Yli-Kauhaluoma, E Bacque, M.G.P Page, F Bjorkling, J.M Tyrrell, J Spencer, P.A Lang, P Baranczewski, R Canton, S.P McElroy, P.S Jones, F Baquero, Edgars Sūna, A Morrison, T.R Walsh, C.J Schofield

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure–activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL–carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models. [Figure not available: see fulltext.]


DOI
10.1038/s41557-021-00831-x
Hipersaite
https://www.nature.com/articles/s41557-021-00831-x

Brem, J., Panduwawala, T., Hansen, J., Hewitt, J., Liepins, E., Donets, P., Espina, L., Farley, A., Shubin, K., Campillos, G., Kiuru, P., Shishodia, S., Krahn, D., Lesniak, R., Schmidt, J., Calvopina, K., Turrientes, M., Kavanagh, M., Lubriks, D., Hinchliffe, P., Langley, G., Aboklaish, A., Eneroth, A., Backlund, M., Baran, A., Nielsen, E., Speake, M., Kuka, J., Robinson, J., Grīnberga], S., Robinson, L., McDonough, M., Rydzik, A., Leissing, T., Jimenez-Castellanos, J., Avison, M., Da Silva Pinto, S., Pannifer, A., Martjuga, M., Widlake, E., Priede, M., Hopkins Navratilova, I., Gniadkowski, M., Belfrage, A., Brandt, P., Yli-Kauhaluoma, J., Bacque, E., Page, M., Bjorkling, F., Tyrrell, J., Spencer, J., Lang, P., Baranczewski, P., Canton, R., McElroy, S., Jones, P., Baquero, F., Sūna, E., Morrison, A., Walsh, T., Schofield, C. Imitation of β-Lactam Binding Enables Broad-Spectrum Metallo-β-Lactamase Inhibitors. Nature Chemistry, 2022, Vol. 14, 15.-24.lpp. ISSN 1755-4330. e-ISSN 1755-4349. Pieejams: doi:10.1038/s41557-021-00831-x

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