7T7G

Imipenem-OXA-23 2 minute complex

7T7G の概要

• エントリーDOI: 10.2210/pdb7t7g/pdb
• 関連するPDBエントリー: 7T7D
• 分子名称: Beta-lactamase OXA-23, (5R)-5-[(1S,2R)-1-formyl-2-hydroxypropyl]-3-[(2-{[(E)-iminomethyl]amino}ethyl)sulfanyl]-4,5-dihydro-1H-pyrrole-2-carbox ylic acid (3 entities in total)
• 機能のキーワード: antibiotic resistance, complex, hydrolase
• 由来する生物種: Acinetobacter baumannii
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 27991.30

構造登録者

Smith, C.A.,Stewart, N.K.,Vakulenko, S.B. (登録日: 2021-12-15, 公開日: 2022-05-04, 最終更新日: 2023-11-15)

主引用文献

Stewart, N.K.,Toth, M.,Alqurafi, M.A.,Chai, W.,Nguyen, T.Q.,Quan, P.,Lee, M.,Buynak, J.D.,Smith, C.A.,Vakulenko, S.B.
C6 Hydroxymethyl-Substituted Carbapenem MA-1-206 Inhibits the Major Acinetobacter baumannii Carbapenemase OXA-23 by Impeding Deacylation.
Mbio, 13:e0036722-e0036722, 2022

PubMed Abstract: Acinetobacter baumannii has become a major nosocomial pathogen, as it is often multidrug-resistant, which results in infections characterized by high mortality rates. The bacterium achieves high levels of resistance to β-lactam antibiotics by producing β-lactamases, enzymes which destroy these valuable agents. Historically, the carbapenem family of β-lactam antibiotics have been the drugs of choice for treating A. baumannii infections. However, their effectiveness has been significantly diminished due to the pathogen's production of carbapenem-hydrolyzing class D β-lactamases (CHDLs); thus, new antibiotics and inhibitors of these enzymes are urgently needed. Here, we describe a new carbapenem antibiotic, MA-1-206, in which the canonical C6 hydroxyethyl group has been replaced with hydroxymethyl. The antimicrobial susceptibility studies presented here demonstrated that this compound is more potent than meropenem and imipenem against A. baumannii producing OXA-23, the most prevalent CHDL of this pathogen, and also against strains producing the CHDL OXA-24/40 and the class B metallo-β-lactamase VIM-2. Our kinetic and mass spectrometry studies revealed that this drug is a reversible inhibitor of OXA-23, where inhibition takes place through a branched pathway. X-ray crystallographic studies, molecular docking, and molecular dynamics simulations of the OXA-23-MA-1-206 complex show that the C6 hydroxymethyl group forms a hydrogen bond with the carboxylated catalytic lysine of OXA-23, effectively preventing deacylation. These results provide a promising strategy for designing a new generation of CHDL-resistant carbapenems to restore their efficacy against deadly A. baumannii infections. Carbapenem antibiotics are the drugs of choice for treatment of deadly infections caused by Gram-negative bacteria. However, their efficacy is severely compromised by the wide spread of carbapenem-hydrolyzing class D β-lactamases (CHDLs). The importance of this research is the discovery that substitution of the canonical hydroxyethyl group of carbapenems by a hydroxymethyl significantly enhances stability against inactivation by the major CHDL of Acinetobacter baumannii, OXA-23. These results provide a novel strategy for designing next-generation, carbapenemase-stable carbapenems to fight multidrug-resistant infections caused by Gram-negative pathogens.

PubMed: 35420470
DOI: 10.1128/mbio.00367-22

実験手法

X-RAY DIFFRACTION (2.5 Å)