Journal Article

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

Krahn, Daniel, Jimenez-Castellanos, Juan Carlos, Kiuru, Paula, Donets, Pawel, Björkling, Fredrik, Suna, Edgars, Hinchliffe, Philip, Shubin, Kirill, Brem, Jürgen, Martjuga, Marina, Tyrrell, Jonathan M., Leśniak, Robert K., Walsh, Timothy R., Avison, Matthew B., Da Silva Pinto, Solange, Belfrage, Anna Karin, Backlund, Maria, Hansen, Jon Ulf, Kavanagh, Madeline E., Robinson, Lindsay, Hewitt, Joanne, Turrientes, María-Carmen, Page, Malcolm G. P., Schmidt (Adrian), Juliane, Baranczewski, Pawel, Jones, Philip S., Calvopiña, Karina, Nielsen, Elisabet I., Aboklaish, Ali F., Cantón, Rafael, Morrison, Angus, Speake, Michael, Liepins, Edgars, Farley, Alistair J. M., Priede, Martins, Langley, Gareth W., Hopkins Navratilova, Iva, Brandt, Peter, Espina, Laura, Baquero, Fernando, McElroy, Stuart P., Yli-Kauhaluoma, Jari, Leissing, Thomas M., Pannifer, Andrew D., Campillos, Gonzalo Gomez, Lubriks, Dmitrijs, Widlake, Emma, Lang, Pauline A., Shishodia, Shifali, Baran, Andrei G., Kuka, Janis, Robinson, John, Panduwawala, Tharindi, Eneroth, Anders, McDonough, Michael A., Rydzik, Anna M., Bacque, Eric, Spencer, James, G

2022

Overview

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. The efficacy of carbapenem antibiotics can be compromised by metallo-β-lactamases, but a high-throughput screen followed by optimization has now enabled the discovery of indole-2-carboxylates (InCs) as potent broad-spectrum metallo-β-lactamase inhibitors. The results highlight the potential of InC–carbapenem combinations for clinical use as well as mechanism-guided approaches to combatting globally disseminated antibiotic resistant mechanisms.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/154/309 / 631/154/309/2144 / 631/154/309/2419 / Amides / Analytical Chemistry / Animal models / Animals / Antibiotic resistance / Antibiotics / Bacteria / beta-Lactamase Inhibitors - chemistry / beta-Lactamase Inhibitors - metabolism / beta-Lactamase Inhibitors - pharmacology / beta-Lactams - metabolism / Binding / Biochemistry / Carbapenems / Carboxylates / Chemistry / Chemistry and Materials Science / Chemistry/Food Science / Crystallography / Drug resistance / Farmaceutisk vetenskap / Gram-negative bacteria / Gram-Negative Bacteria - drug effects / Humans / Inhibitors / Inorganic Chemistry / Meropenem / Metallo-β-lactamase / Metallography / Mice / Microbial Sensitivity Tests / Multidrug resistance / Optimization / Organic Chemistry / Peritonitis / Pharmaceutical Science / Physical Chemistry / Protein Binding / Structure-Activity Relationship / Thigh / β Lactamase / β-Lactam antibiotics