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8CUQ

X-ray crystal structure of ADC-33 in complex with sulfonamidoboronic acid 6e

8CUQ の概要
エントリーDOI10.2210/pdb8cuq/pdb
分子名称Beta-lactamase, 3-[(4R)-4-ethyl-5,7,7-trihydroxy-2,2,7-trioxo-6-oxa-2lambda~6~-thia-3-aza-7lambda~5~-phospha-5-boraheptan-1-yl]benzoic acid (3 entities in total)
機能のキーワードcephalasporinase, inhibitor, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
由来する生物種Acinetobacter baumannii
タンパク質・核酸の鎖数2
化学式量合計82391.31
構造登録者
Fernando, M.C.,Wallar, B.J.,Powers, R.A. (登録日: 2022-05-17, 公開日: 2023-04-05, 最終更新日: 2024-10-16)
主引用文献Introvigne, M.L.,Beardsley, T.J.,Fernando, M.C.,Leonard, D.A.,Wallar, B.J.,Rudin, S.D.,Taracila, M.A.,Rather, P.N.,Colquhoun, J.M.,Song, S.,Fini, F.,Hujer, K.M.,Hujer, A.M.,Prati, F.,Powers, R.A.,Bonomo, R.A.,Caselli, E.
Sulfonamidoboronic Acids as "Cross-Class" Inhibitors of an Expanded-Spectrum Class C Cephalosporinase, ADC-33, and a Class D Carbapenemase, OXA-24/40: Strategic Compound Design to Combat Resistance in Acinetobacter baumannii .
Antibiotics, 12:-, 2023
Cited by
PubMed Abstract: is a Gram-negative organism listed as an urgent threat pathogen by the World Health Organization (WHO). Carbapenem-resistant (CRAB), especially, present therapeutic challenges due to complex mechanisms of resistance to -lactams. One of the most important mechanisms is the production of -lactamase enzymes capable of hydrolyzing -lactam antibiotics. Co-expression of multiple classes of -lactamases is present in CRAB; therefore, the design and synthesis of "cross-class" inhibitors is an important strategy to preserve the efficacy of currently available antibiotics. To identify new, nonclassical -lactamase inhibitors, we previously identified a sulfonamidomethaneboronic acid active against -derived class C -lactamases (ADC-7). The compound demonstrated affinity for ADC-7 with a = 160 nM and proved to be able to decrease MIC values of ceftazidime and cefotaxime in different bacterial strains. Herein, we describe the activity of against other -lactamases in : the cefepime-hydrolysing class C extended-spectrum -lactamase (ESAC) ADC-33 and the carbapenem-hydrolyzing OXA-24/40 (class D). These investigations demonstrate as a valuable cross-class (C and D) inhibitor, and the paper describes our attempts to further improve its activity. Five chiral analogues of were rationally designed and synthesized. The structures of OXA-24/40 and ADC-33 in complex with and select chiral analogues were obtained. The structure activity relationships (SARs) are highlighted, offering insights into the main determinants for cross-class C/D inhibitors and impetus for novel drug design.
PubMed: 37107006
DOI: 10.3390/antibiotics12040644
主引用文献が同じPDBエントリー
実験手法
X-RAY DIFFRACTION (1.55 Å)
構造検証レポート
Validation report summary of 8cuq
検証レポート(詳細版)ダウンロードをダウンロード

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件を2025-07-16に公開中

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