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Title: Structure-Based Analysis of Boronic Acids as Inhibitors of Acinetobacter-Derived Cephalosporinase-7, a Unique Class C β-Lactamase

Journal Article · · ACS Infectious Diseases
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  1. Grand Valley State Univ., Allendale, MI (United States)
  2. Louis Stokes Cleveland Dept. of Veterans Affairs Medical Center, Cleveland, OH (United States); Case Western Reserve Univ. School of Medicine, Cleveland, OH (United States)
  3. Univ. of Modena and Reggio Emilia (Italy)
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Acinetobacter baumannii is a multidrug resistant pathogen that infects more than 12 000 patients each year in the US. Much of the resistance to β-lactam antibiotics in Acinetobacter spp. is mediated by class C β-lactamases known as Acinetobacter-derived cephalosporinases (ADCs). ADCs are unaffected by clinically used β-lactam-based β-lactamase inhibitors. In this study, five boronic acid transition state analog inhibitors (BATSIs) were evaluated for inhibition of the class C cephalosporinase ADC-7. Our goal was to explore the properties of BATSIs designed to probe the R1 binding site. Ki values ranged from low micromolar to subnanomolar, and circular dichroism (CD) demonstrated that each inhibitor stabilizes the β-lactamase–inhibitor complexes. Additionally, X-ray crystal structures of ADC-7 in complex with five inhibitors were determined (resolutions from 1.80 to 2.09 Å). In the ADC-7/CR192 complex, the BATSI with the lowest Ki (0.45 nM) and greatest ΔTm (+9 °C), a trifluoromethyl substituent, interacts with Arg340. Arg340 is unique to ADCs and may play an important role in the inhibition of ADC-7. Here, the ADC-7/BATSI complexes determined in this study shed light into the unique recognition sites in ADC enzymes and also offer insight into further structure-based optimization of these inhibitors.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Inst. of Allergy and Infectious Diseases of the National Inst. of Health; Michigan Economic Development Corporation; Michigan Technology Tri-Corridor
Grant/Contract Number:
AC02-06CH11357; R01 AI072219; R15 AI094489; 085P1000817
OSTI ID:
1431376
Journal Information:
ACS Infectious Diseases, Vol. 4, Issue 3; ISSN 2373-8227
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 17 works
Citation information provided by
Web of Science

References (33)

Origins and Evolution of Antibiotic Resistance journal August 2010
Mechanisms of Multidrug Resistance in Acinetobacter Species and Pseudomonas aeruginosa journal September 2006
Why are we afraid of Acinetobacter baumannii? journal June 2008
Carbapenem-resistant Acinetobacter baumannii and Klebsiella pneumoniae across a hospital system: impact of post-acute care facilities on dissemination journal May 2010
Global Challenge of Multidrug-Resistant Acinetobacter baumannii journal July 2007
New Insights into Dissemination and Variation of the Health Care-Associated Pathogen Acinetobacter baumannii from Genomic Analysis journal January 2014
Beta-lactamase-mediated resistance and opportunities for its control journal June 1998
Identification of a New Allelic Variant of the Acinetobacter baumannii Cephalosporinase, ADC-7 β-Lactamase: Defining a Unique Family of Class C Enzymes journal July 2005
Extended-Spectrum AmpC Cephalosporinase in Acinetobacter baumannii: ADC-56 Confers Resistance to Cefepime journal July 2011
Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumannii journal November 2014
Three Decades of  -Lactamase Inhibitors journal January 2010
β-lactamase inhibitors. The inhibition of serine β-lactamases by specific boronic acids journal April 1988
Design, Synthesis, and Crystal Structures of 6-Alkylidene-2′-Substituted Penicillanic Acid Sulfones as Potent Inhibitors of Acinetobacter baumannii OXA-24 Carbapenemase journal September 2010
Inhibition of a class C beta-lactamase by a specific phosphonate monoester journal November 1989
O -Aryloxycarbonyl Hydroxamates:  New β-Lactamase Inhibitors That Cross-Link the Active Site journal August 2007
Diazabicyclooctanes (DBOs): a potent new class of non-β-lactam β-lactamase inhibitors journal October 2011
Structural and Kinetic Characterization of Diazabicyclooctanes as Dual Inhibitors of Both Serine-β-Lactamases and Penicillin-Binding Proteins journal January 2016
Fragment-guided design of subnanomolar  -lactamase inhibitors active in vivo journal October 2012
Structure-based optimization of cephalothin-analogue boronic acids as β-lactamase inhibitors journal February 2008
Structural Milestones in the Reaction Pathway of an Amide Hydrolase journal March 2002
Synthesis of [(1,2,3-Triazol-1-yl)methyl]boronic Acids Through Click Chemistry: Easy Access to a Potential Scaffold for Protease Inhibitors: Synthesis of [(1,2,3-Triazol-1-yl)methyl]boronic Acids journal January 2015
Engagement of CF 3 Group in N–H···F–C Hydrogen Bond in the Solution State: NMR Spectroscopy and MD Simulation Studies journal January 2013
Expansion of the σ-hole concept journal December 2008
The origins of the directionality of noncovalent intermolecular interactions # journal May 2015
Halogen Interactions in Protein–Ligand Complexes: Implications of Halogen Bonding for Rational Drug Design journal November 2013
Face-to-Face and Edge-to-Face π−π Interactions in a Synthetic DNA Hairpin with a Stilbenediether Linker journal September 2003
π-Stacking Interactions: ALIVE AND WELL IN PROTEINS journal June 1998
Effects of Heteroatoms on Aromatic π−π Interactions: Benzene−Pyridine and Pyridine Dimer journal February 2009
Identification of 50 Class D β-Lactamases and 65 Acinetobacter-Derived Cephalosporinases in Acinetobacter spp. journal November 2013
Refinement of Macromolecular Structures by the Maximum-Likelihood Method journal May 1997
Phaser crystallographic software journal July 2007
Coot model-building tools for molecular graphics journal November 2004
Functional analyses of AmpC β-lactamase through differential stability journal January 1999

Cited By (4)

Deciphering the Evolution of Cephalosporin Resistance to Ceftolozane-Tazobactam in Pseudomonas aeruginosa journal December 2018
Exploring Additional Dimensions of Complexity in Inhibitor Design for Serine β-Lactamases: Mechanistic and Intra- and Inter-molecular Chemistry Approaches journal April 2018
β-lactam/β-lactamase inhibitor combinations: an update journal January 2018
Structures of FOX-4 Cephamycinase in Complex with Transition-State Analog Inhibitors journal April 2020

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
β-lactamase
cephalosporinase
boronic acid
transition state analog
inhibitors
Acinetobacter
ADC-7