38. Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors

Brem, J.; Panduwawala, T.; Hansen, J. U.; Hewitt, J.; Liepins, E.; Donets, P.; Espina, L.; Farley, A. J. M.; Shubin, K; Campillos, G. G.; Kiuru, P.; Shishodia, S.; Krahn, D.; Leśniak, R. K.; Schmidt (Adrian), J.; Calvopiña, K.; Turrientes, M. C.; Kavanagh, M. E.; Lubriks, D.; Hinchliffe, P.; Langley, G. W.; Aboklaish, A. F.; Eneroth, A.; Backlund, M.; Baran, A. G.; Nielsen, E. I.; Speake, M.; Kuka, J.; Robinson, J.; Grinberga, S.; Robinson, L.; McDonough, M. A.; Rydzik, A. M.; Leissing, T. M.; Jimenez-Castellanos, J. C.; Avison, M. B; Pinto, S. S.; Pannifer, A. D.; Martjuga, M.; Widlake, E.; Priede, M.; Navratilova, I. H.; Gniadkowski, M.; Belfrage, A. K.; Brandt, P.; Yli-Kauhaluoma, j.; Bacque, E.; Page, M. G. P.; Björkling, F.; Tyrrell, J. M.; Spencer, J.; Lang, P. A.; Baranczewski, P.; Cantón, R.; McElroy, S. P.; Jones, P. S.; Baquero, F.; Suna, E.; Morrison, A.; Walsh, T. R.; Schofield, C. J. Nat. Chem 2021.

DOI: 10.1038/s41557-021-00831-x

Abstract

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.