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

Antimicrobial Agents and Chemotherapy
Pauline A LangJürgen Brem

Abstract

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 great...Continue Reading

References

Jan 1, 1979·Methods in Enzymology·J W Williams, J F Morrison
May 1, 1977·Antimicrobial Agents and Chemotherapy·C Reading, M Cole
Jan 1, 1988·Advances in Enzymology and Related Areas of Molecular Biology·J F Morrison, C T Walsh
Apr 2, 1999·Antimicrobial Agents and Chemotherapy·E C Nelson, B G Elisha
Oct 24, 2002·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsThomas C Terwilliger
Mar 26, 2004·Nature Reviews. Microbiology·James B KaperHarry L Mobley
Aug 5, 2006·Nature Reviews. Drug Discovery·Robert A CopelandThomas D Meek
Jan 13, 2009·Clinical Microbiology Reviews·George A Jacoby
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Dec 8, 2009·Nature Reviews. Microbiology·Matthew A Croxen, B Brett Finlay
Dec 10, 2009·Antimicrobial Agents and Chemotherapy·Karen Bush, George A Jacoby
Jan 13, 2010·Clinical Microbiology Reviews·Sarah M Drawz, Robert A Bonomo
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Jul 29, 2010·Current Opinion in Chemical Biology·Hao Lu, Peter J Tonge
Jun 15, 2011·Analytical Biochemistry·Robert A CopelandMargaret Porter Scott
Jul 4, 2012·Proceedings of the National Academy of Sciences of the United States of America·David E EhmannStewart L Fisher
Aug 1, 2013·Journal of Medicinal Chemistry·Sander S van BerkelChristopher J Schofield
Aug 6, 2013·The Journal of Biological Chemistry·David E EhmannStewart L Fisher
Oct 5, 2013·Clinical Microbiology Reviews·Matthew A CroxenB Brett Finlay
Jan 18, 2014·Bioorganic & Medicinal Chemistry Letters·Timothy A BlizzardMilton L Hammond
Jun 20, 2015·The Journal of Antimicrobial Chemotherapy·Akihiro MorinakaDavid M Livermore
Nov 18, 2015·Antimicrobial Agents and Chemotherapy·Abdelhamid AsliFrançois Malouin
Apr 14, 2016·Organic & Biomolecular Chemistry·Hwanho ChoiChristopher J Schofield
Jun 22, 2016·Future Medicinal Chemistry·David Yuxin WangChristopher J Schofield
Apr 10, 2015·ACS Infectious Diseases·Dustin T KingNatalie C J Strynadka
Feb 9, 2017·Acta Crystallographica. Section D, Structural Biology·Dorothee LiebschnerPaul D Adams
Jun 24, 2017·ACS Chemical Neuroscience·Peter J Tonge
Jul 6, 2017·Organic & Biomolecular Chemistry·Christopher T LohansChristopher J Schofield
Jul 26, 2017·Antimicrobial Agents and Chemotherapy·Wanchun JinYoshichika Arakawa
Feb 15, 2018·Antimicrobial Agents and Chemotherapy·Michiyoshi NukagaRobert A Bonomo
Aug 1, 2018·Antimicrobial Agents and Chemotherapy·Karen Bush
Mar 13, 2019·ACS Infectious Diseases·Folkert ReckQin Yue
Jun 27, 2019·Antimicrobial Agents and Chemotherapy·Melina RuggieroPablo Power

❮ Previous
Next ❯

Citations

Dec 10, 2020·International Journal of Molecular Sciences·Juan C Vázquez-UchaAlejandro Beceiro

❮ Previous
Next ❯

Software Mentioned

MassHunter Qualitative Analysis
MassHunter Workstation Qualitative Analysis
Coot
PHENIX

Related Concepts

Related Feeds

CRISPR Screens in Drug Resistance

CRISPR-Cas system enables the editing of genes to create or correct mutations. This feed focuses on the application of CRISPR-Cas system in high-throughput genome-wide screens to identify genes that may confer drug resistance.

Beta-lactamase Inhibitors (ASM)

Beta-lactamase inhibitors are a class of antibiotics that inhibit beta-lactamases, a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. Here is the latest research.

Beta-lactamase Inhibitors

Beta-lactamase inhibitors are a class of antibiotics that inhibit beta-lactamases, a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. Here is the latest research.

Related Papers

Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America
Pranita D TammaAntibacterial Resistance Leadership Group
FEMS Microbiology Letters
Dobryan M TraczCanadian Nosocomial Infection Surveillance Program
© 2021 Meta ULC. All rights reserved