Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

Structures of FOX-4 Cephamycinase in Complex with Transition-State Analog Inhibitors

Journal Article · · Biomolecules
DOI:https://doi.org/10.3390/biom10050671· OSTI ID:1834814
 [1];  [2];  [3];  [4];  [1];  [5];  [4];  [2];  [4];  [6]
  1. Hofstra Univ., Hempstead, NY (United States). Dept. of Chemistry
  2. Univ. of Modena and Reggio Emilia, Modena (Italy). Dept. of Life Sciences
  3. Case Western Reserve Univ. School of Medicine, Cleveland, OH (United States). Dept. of Medicine; Louis Stokes Cleveland Dept. of Veterans Affairs Medical Center, Cleveland, OH (United States)
  4. Albert Einstein College of Medicine, Bronx, NY (United States). Dept. of Biochemistry
  5. Case Western Reserve Univ. School of Medicine, Cleveland, OH (United States). Dept. of Medicine. Dept. of Biochemistry; Louis Stokes Cleveland Dept. of Veterans Affairs Medical Center, Cleveland, OH (United States)
  6. Case Western Reserve Univ. School of Medicine, Cleveland, OH (United States). Dept. of Medicine. Dept. of Biochemistry. Dept. of Pharmacology. Dept. of Molecular Biology and Microbiology. Dept. of Proteomics and Bioinformatics; Louis Stokes Cleveland Dept. of Veterans Affairs Medical Center, Cleveland, OH (United States); CWRU-Cleveland VAMC Center for Antimicrobial Resistance and Epidemiology (Case VA CARES), Cleveland, OH (United States)
+ Show Author Affiliations
Boronic acid transition-state analog inhibitors (BATSIs) are partners with β-lactam antibiotics for the treatment of complex bacterial infections. Herein, microbiological, biochemical, and structural findings on four BATSIs with the FOX-4 cephamycinase, a class C β-lactamase that rapidly hydrolyzes cefoxitin, are revealed. FOX-4 is an extended-spectrum class C cephalosporinase that demonstrates conformational flexibility when complexed with certain ligands. Like other β-lactamases of this class, studies on FOX-4 reveal important insights into structure–activity relationships. We show that SM23, a BATSI, shows both remarkable flexibility and affinity, binding similarly to other β-lactamases, yet retaining an IC50 value < 0.1 μM. Our analyses open up new opportunities for the design of novel transition-state analogs of class C enzymes.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC)
OSTI ID:
1834814
Alternate ID(s):
OSTI ID: 1836738
Journal Information:
Biomolecules, Journal Name: Biomolecules Journal Issue: 5 Vol. 10; ISSN 2218-273X
Publisher:
MDPICopyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (55)

Studies on the inhibition of AmpC and other β-lactamases by cyclic boronates journal April 2019
Energetic, structural, and antimicrobial analyses of β-lactam side chain recognition by β-lactamases journal January 2001
Structure-based design and in-parallel synthesis of inhibitors of AmpC β-lactamase journal June 2001
Structure-Based Analysis of Boronic Acids as Inhibitors of Acinetobacter -Derived Cephalosporinase-7, a Unique Class C β-Lactamase journal November 2017
X-ray Crystallography Deciphers the Activity of Broad-Spectrum Boronic Acid β-Lactamase Inhibitors journal March 2019
Structures of Ceftazidime and Its Transition-State Analogue in Complex with AmpC β-Lactamase:  Implications for Resistance Mutations and Inhibitor Design † , ‡ journal August 2001
Structure, Function, and Inhibition along the Reaction Coordinate of CTX-M β-Lactamases journal April 2005
Optimizing Cell Permeation of an Antibiotic Resistance Inhibitor for Improved Efficacy journal October 2007
Targeting Class A and C Serine β-Lactamases with a Broad-Spectrum Boronic Acid Derivative journal June 2014
β-lactamase inhibitors. The inhibition of serine β-lactamases by specific boronic acids journal April 1988
A solution for the best rotation to relate two sets of vectors journal September 1976
Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions journal November 2004
Overview of the CCP 4 suite and current developments journal March 2011
Carbapenems: Past, Present, and Future journal August 2011
New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World journal December 2013
Structural Basis for Imipenem Inhibition of Class C  -Lactamases journal December 2002
Three Decades of  -Lactamase Inhibitors journal January 2010
Exploring the potential of boronic acids as inhibitors of OXA-24/40 β-lactamase: Boronic Acid Inhibitors of OXA-24/40 journal February 2017
Exploring sequence requirements for C 3 /C 4 carboxylate recognition in the Pseudomonas aeruginosa cephalosporinase: Insights into plasticity of the AmpC β-lactamase: C 3 /C 4 Carboxylate Recognition in P. aeruginosa AmpC journal May 2011
Imipenem–Relebactam and Meropenem–Vaborbactam: Two Novel Carbapenem-β-Lactamase Inhibitor Combinations journal December 2017
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
Structural Milestones in the Reaction Pathway of an Amide Hydrolase journal March 2002
Energetic, structural, and antimicrobial analyses of β-lactam side chain recognition by β-lactamases journal January 2001
Structure-based design and in-parallel synthesis of inhibitors of AmpC β-lactamase journal June 2001
Will morphing boron-based inhibitors beat the β-lactamases? journal June 2019
New β-Lactamase Inhibitors in the Clinic journal June 2016
Discovery of a Cyclic Boronic Acid β-Lactamase Inhibitor (RPX7009) with Utility vs Class A Serine Carbapenemases journal March 2015
Bicyclic Boronate VNRX-5133 Inhibits Metallo- and Serine-β-Lactamases journal August 2019
Discovery of Cyclic Boronic Acid QPX7728, an Ultrabroad-Spectrum Inhibitor of Serine and Metallo-β-lactamases journal March 2020
Inhibition of Acinetobacter -Derived Cephalosporinase: Exploring the Carboxylate Recognition Site Using Novel β-Lactamase Inhibitors journal November 2017
Game Changers: New β-Lactamase Inhibitor Combinations Targeting Antibiotic Resistance in Gram-Negative Bacteria journal December 2017
Structure-Based Design Guides the Improved Efficacy of Deacylation Transition State Analogue Inhibitors of TEM-1 β-Lactamase † , # journal May 2000
Nanomolar Inhibitors of AmpC β-Lactamase journal December 2002
The Deacylation Mechanism of AmpC β-Lactamase at Ultrahigh Resolution journal February 2006
Structure-Based Enhancement of Boronic Acid-Based Inhibitors of AmpC β-Lactamase journal November 1998
Structural basis of metallo-β-lactamase, serine-β-lactamase and penicillin-binding protein inhibition by cyclic boronates journal August 2016
A tripeptide deletion in the R2 loop of the class C  -lactamase enzyme FOX-4 impairs cefoxitin hydrolysis and slightly increases susceptibility to  -lactamase inhibitors journal April 2010
Phaser crystallographic software journal July 2007
A solution for the best rotation to relate two sets of vectors journal September 1976
PHENIX : building new software for automated crystallographic structure determination journal October 2002
Coot model-building tools for molecular graphics journal November 2004
Secondary-structure matching (SSM), a new tool for fast protein structure alignment in three dimensions journal November 2004
MolProbity : all-atom structure validation for macromolecular crystallography journal December 2009
Overview of the CCP 4 suite and current developments journal March 2011
Refinement of Macromolecular Structures by the Maximum-Likelihood Method journal May 1997
Biochemical Characterization of QPX7728, a New Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases journal March 2020
Carbapenems: Past, Present, and Future journal August 2011
New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World journal December 2013
Analysis of the Structure and Function of FOX-4 Cephamycinase journal February 2016
Cyclic Boronates Inhibit All Classes of β-Lactamases journal January 2017
Crystal Structures of KPC-2 and SHV-1 β-Lactamases in Complex with the Boronic Acid Transition State Analog S02030 journal January 2016
Molecular Characterization of FOX-4, a New AmpC-Type Plasmid-Mediated β-Lactamase from an Escherichia coli Strain Isolated in Spain journal September 2000
Structural Basis for Imipenem Inhibition of Class C  -Lactamases journal December 2002
AmpC  -Lactamases journal January 2009
Three Decades of  -Lactamase Inhibitors journal January 2010

Similar Records

Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumannii
Journal Article · Thu Nov 06 19:00:00 EST 2014 · Biochemistry · OSTI ID:1168844
Analysis of the Structure and Function of FOX-4 Cephamycinase
Journal Article · Sun Nov 01 19:00:00 EST 2015 · Antimicrobial Agents and Chemotherapy · OSTI ID:1243116
Structure-Based Analysis of Boronic Acids as Inhibitors of Acinetobacter-Derived Cephalosporinase-7, a Unique Class C β-Lactamase
Journal Article · Wed Nov 15 19:00:00 EST 2017 · ACS Infectious Diseases · OSTI ID:1431376

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
boronic acid
cephamycinase
transition-state analog inhibitor
β-lactam
β-lactamase