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Structural Investigations of the Inhibition of Escherichia coli AmpC β-Lactamase by Diazabicyclooctanes.

التفاصيل البيبلوغرافية
العنوان: Structural Investigations of the Inhibition of Escherichia coli AmpC β-Lactamase by Diazabicyclooctanes.
المؤلفون: Lang PA; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom., Leissing TM; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom., Page MGP; Jacobs University Bremen gGmbH, Bremen, Germany., Schofield CJ; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom christopher.schofield@chem.ox.ac.uk jurgen.brem@chem.ox.ac.uk., Brem J; Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford, United Kingdom christopher.schofield@chem.ox.ac.uk jurgen.brem@chem.ox.ac.uk.
المصدر: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2021 Jan 20; Vol. 65 (2). Date of Electronic Publication: 2021 Jan 20 (Print Publication: 2021).
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 0315061 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1098-6596 (Electronic) Linking ISSN: 00664804 NLM ISO Abbreviation: Antimicrob Agents Chemother Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, American Society for Microbiology
مواضيع طبية MeSH: Escherichia coli*/genetics , beta-Lactamase Inhibitors*/pharmacology, Anti-Bacterial Agents/pharmacology ; Azabicyclo Compounds/pharmacology ; Bacterial Proteins/genetics ; Microbial Sensitivity Tests ; beta-Lactamases/genetics
مستخلص: β-Lactam antibiotics are presently the most important treatments for infections by pathogenic Escherichia coli , but their use is increasingly compromised by β-lactamases, including the chromosomally encoded class C AmpC serine-β-lactamases (SBLs). The diazabicyclooctane (DBO) avibactam is a potent AmpC inhibitor; the clinical success of avibactam combined with ceftazidime has stimulated efforts to optimize the DBO core. We report kinetic and structural studies, including four high-resolution crystal structures, concerning inhibition of the AmpC serine-β-lactamase from E. coli (AmpC EC ) by clinically relevant DBO-based inhibitors: avibactam, relebactam, nacubactam, and zidebactam. Kinetic analyses and mass spectrometry-based assays were used to study their mechanisms of AmpC EC inhibition. The results reveal that, under our assay conditions, zidebactam manifests increased potency (apparent inhibition constant [ K iapp ], 0.69 μM) against AmpC EC compared to that of the other DBOs ( K iapp = 5.0 to 7.4 μM) due to an ∼10-fold accelerated carbamoylation rate. However, zidebactam also has an accelerated off-rate, and with sufficient preincubation time, all the DBOs manifest similar potencies. Crystallographic analyses indicate a greater conformational freedom of the AmpC EC -zidebactam carbamoyl complex compared to those for the other DBOs. The results suggest the carbamoyl complex lifetime should be a consideration in development of DBO-based SBL inhibitors for the clinically important class C SBLs.
(Copyright © 2021 Lang et al.)
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معلومات مُعتمدة: 099141/Z/12/Z United Kingdom WT_ Wellcome Trust; MC_PC_16092 United Kingdom MRC_ Medical Research Council; United Kingdom WT_ Wellcome Trust; MRF_MRF-145-0004-TPG-AVISO United Kingdom MRF MRF; BB/R000344/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; 106244/Z/14/Z United Kingdom WT_ Wellcome Trust; MR/S014934/1 United Kingdom MRC_ Medical Research Council
فهرسة مساهمة: Keywords: Avycaz; antimicrobial resistance; avibactam; cephalosporin resistance; diazabicyclooctane; nacubactam; relebactam; serine β-lactamase inhibitors; zidebactam
المشرفين على المادة: 0 (Anti-Bacterial Agents)
0 (Azabicyclo Compounds)
0 (Bacterial Proteins)
0 (beta-Lactamase Inhibitors)
EC 3.5.2.6 (AmpC beta-lactamases)
EC 3.5.2.6 (beta-Lactamases)
تواريخ الأحداث: Date Created: 20201117 Date Completed: 20210617 Latest Revision: 20220720
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC7849013
DOI: 10.1128/AAC.02073-20
PMID: 33199391
قاعدة البيانات: MEDLINE
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