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
Hyperlink
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, pp.15-24. ISSN 1755-4330. e-ISSN 1755-4349. Available from: doi:10.1038/s41557-021-00831-x
Publication language
English (en)