7AFZ

L1 metallo-b-lactamase with compound EBL-1306

7AFZ の概要

• エントリーDOI: 10.2210/pdb7afz/pdb
• 分子名称: Metallo-beta-lactamase L1, ZINC ION, 3-[3-chloranyl-4-(methylsulfonylmethyl)phenyl]-7-propan-2-yl-1~{H}-indole-2-carboxylic acid, ... (5 entities in total)
• 機能のキーワード: inhibitor, lactamase, antibiotic resistance, indole, antimicrobial protein
• 由来する生物種: Stenotrophomonas maltophilia (Pseudomonas maltophilia)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29623.46

構造登録者

Hinchliffe, P.,Spencer, J.,Brem, J. (登録日: 2020-09-21, 公開日: 2021-10-06, 最終更新日: 2024-11-06)

主引用文献

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.,Lesniak, R.K.,Schmidt Adrian, J.,Calvopina, 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.,Da Silva Pinto, S.,Pannifer, A.D.,Martjuga, M.,Widlake, E.,Priede, M.,Hopkins Navratilova, I.,Gniadkowski, M.,Belfrage, A.K.,Brandt, P.,Yli-Kauhaluoma, J.,Bacque, E.,Page, M.G.P.,Bjorkling, F.,Tyrrell, J.M.,Spencer, J.,Lang, P.A.,Baranczewski, P.,Canton, R.,McElroy, S.P.,Jones, P.S.,Baquero, F.,Suna, E.,Morrison, A.,Walsh, T.R.,Schofield, C.J.
Imitation of beta-lactam binding enables broad-spectrum metallo-beta-lactamase inhibitors.
Nat.Chem., 14:15-24, 2022

PubMed 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.

PubMed: 34903857
DOI: 10.1038/s41557-021-00831-x

実験手法

X-RAY DIFFRACTION (1.5 Å)