| Literature DB >> 34903857 |
Jürgen Brem1, Tharindi Panduwawala2, Jon Ulf Hansen3, Joanne Hewitt4, Edgars Liepins5, Pawel Donets5, Laura Espina6, Alistair J M Farley2, Kirill Shubin5, Gonzalo Gomez Campillos2, Paula Kiuru7, Shifali Shishodia2,8, Daniel Krahn2, Robert K Leśniak2, Juliane Schmidt Adrian2, Karina Calvopiña2, María-Carmen Turrientes9, Madeline E Kavanagh2,10, Dmitrijs Lubriks5, Philip Hinchliffe11, Gareth W Langley2,12, Ali F Aboklaish6, Anders Eneroth13, Maria Backlund13, Andrei G Baran5, Elisabet I Nielsen14, Michael Speake4,15, Janis Kuka5, John Robinson4,15, Solveiga Grinberga5, Lindsay Robinson4,15, Michael A McDonough2, Anna M Rydzik2,16, Thomas M Leissing2, Juan Carlos Jimenez-Castellanos11,17, Matthew B Avison11, Solange Da Silva Pinto2, Andrew D Pannifer4, Marina Martjuga5, Emma Widlake6, Martins Priede5, Iva Hopkins Navratilova4, Marek Gniadkowski18, Anna Karin Belfrage19, Peter Brandt19,20, Jari Yli-Kauhaluoma7, Eric Bacque21, Malcolm G P Page22, Fredrik Björkling23, Jonathan M Tyrrell6,11, James Spencer11, Pauline A Lang2, Pawel Baranczewski24, Rafael Cantón9, Stuart P McElroy4,15, Philip S Jones4,15, Fernando Baquero9, Edgars Suna5, Angus Morrison4,15, Timothy R Walsh6, Christopher J Schofield25.
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.Entities:
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Year: 2021 PMID： 34903857 DOI： 10.1038/s41557-021-00831-x
Source DB: PubMed Journal: Nat Chem ISSN： 1755-4330 Impact factor: 24.427