Structure-Based Analysis of Boronic Acids as Inhibitors of Acinetobacter-Derived Cephalosporinase-7, a Unique Class C β-Lactamase
Abstract
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.
- Authors:
-
- Grand Valley State Univ., Allendale, MI (United States)
- Louis Stokes Cleveland Dept. of Veterans Affairs Medical Center, Cleveland, OH (United States); Case Western Reserve Univ. School of Medicine, Cleveland, OH (United States)
- Univ. of Modena and Reggio Emilia (Italy)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- 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
- OSTI Identifier:
- 1431376
- Grant/Contract Number:
- AC02-06CH11357; R01 AI072219; R15 AI094489; 085P1000817
- Resource Type:
- Journal Article: Accepted Manuscript
- Journal Name:
- ACS Infectious Diseases
- Additional Journal Information:
- Journal Volume: 4; Journal Issue: 3; Journal ID: ISSN 2373-8227
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; β-lactamase; cephalosporinase; boronic acid; transition state analog; inhibitors; Acinetobacter; ADC-7
Citation Formats
Bouza, Alexandra A., Swanson, Hollister C., Smolen, Kali A., VanDine, Alison L., Taracila, Magdalena A., Romagnoli, Chiara, Caselli, Emilia, Prati, Fabio, Bonomo, Robert A., Powers, Rachel A., and Wallar, Bradley J. Structure-Based Analysis of Boronic Acids as Inhibitors of Acinetobacter-Derived Cephalosporinase-7, a Unique Class C β-Lactamase. United States: N. p., 2017.
Web. doi:10.1021/acsinfecdis.7b00152.
Bouza, Alexandra A., Swanson, Hollister C., Smolen, Kali A., VanDine, Alison L., Taracila, Magdalena A., Romagnoli, Chiara, Caselli, Emilia, Prati, Fabio, Bonomo, Robert A., Powers, Rachel A., & Wallar, Bradley J. Structure-Based Analysis of Boronic Acids as Inhibitors of Acinetobacter-Derived Cephalosporinase-7, a Unique Class C β-Lactamase. United States. https://doi.org/10.1021/acsinfecdis.7b00152
Bouza, Alexandra A., Swanson, Hollister C., Smolen, Kali A., VanDine, Alison L., Taracila, Magdalena A., Romagnoli, Chiara, Caselli, Emilia, Prati, Fabio, Bonomo, Robert A., Powers, Rachel A., and Wallar, Bradley J. 2017.
"Structure-Based Analysis of Boronic Acids as Inhibitors of Acinetobacter-Derived Cephalosporinase-7, a Unique Class C β-Lactamase". United States. https://doi.org/10.1021/acsinfecdis.7b00152. https://www.osti.gov/servlets/purl/1431376.
@article{osti_1431376,
title = {Structure-Based Analysis of Boronic Acids as Inhibitors of Acinetobacter-Derived Cephalosporinase-7, a Unique Class C β-Lactamase},
author = {Bouza, Alexandra A. and Swanson, Hollister C. and Smolen, Kali A. and VanDine, Alison L. and Taracila, Magdalena A. and Romagnoli, Chiara and Caselli, Emilia and Prati, Fabio and Bonomo, Robert A. and Powers, Rachel A. and Wallar, Bradley J.},
abstractNote = {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.},
doi = {10.1021/acsinfecdis.7b00152},
url = {https://www.osti.gov/biblio/1431376},
journal = {ACS Infectious Diseases},
issn = {2373-8227},
number = 3,
volume = 4,
place = {United States},
year = {Thu Nov 16 00:00:00 EST 2017},
month = {Thu Nov 16 00:00:00 EST 2017}
}
Web of Science
Works referenced in this record:
Origins and Evolution of Antibiotic Resistance
journal, August 2010
- Davies, J.; Davies, D.
- Microbiology and Molecular Biology Reviews, Vol. 74, Issue 3
Mechanisms of Multidrug Resistance in Acinetobacter Species and Pseudomonas aeruginosa
journal, September 2006
- Bonomo, Robert A.; Szabo, Dora
- Clinical Infectious Diseases, Vol. 43, Issue Supplement_2
Why are we afraid of Acinetobacter baumannii?
journal, June 2008
- Perez, Federico; Endimiani, Andrea; Bonomo, Robert A.
- Expert Review of Anti-infective Therapy, Vol. 6, Issue 3
Carbapenem-resistant Acinetobacter baumannii and Klebsiella pneumoniae across a hospital system: impact of post-acute care facilities on dissemination
journal, May 2010
- Perez, F.; Endimiani, A.; Ray, A. J.
- Journal of Antimicrobial Chemotherapy, Vol. 65, Issue 8
Global Challenge of Multidrug-Resistant Acinetobacter baumannii
journal, July 2007
- Perez, Federico; Hujer, Andrea M.; Hujer, Kristine M.
- Antimicrobial Agents and Chemotherapy, Vol. 51, Issue 10
New Insights into Dissemination and Variation of the Health Care-Associated Pathogen Acinetobacter baumannii from Genomic Analysis
journal, January 2014
- Wright, Meredith S.; Haft, Daniel H.; Harkins, Derek M.
- mBio, Vol. 5, Issue 1
Beta-lactamase-mediated resistance and opportunities for its control
journal, June 1998
- Livermore, D. M.
- Journal of Antimicrobial Chemotherapy, Vol. 41, Issue suppl 4
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
- Hujer, Kristine M.; Hamza, Nashaat S.; Hujer, Andrea M.
- Antimicrobial Agents and Chemotherapy, Vol. 49, Issue 7
Extended-Spectrum AmpC Cephalosporinase in Acinetobacter baumannii: ADC-56 Confers Resistance to Cefepime
journal, July 2011
- Tian, Guo-Bao; Adams-Haduch, Jennifer M.; Taracila, Magdalena
- Antimicrobial Agents and Chemotherapy, Vol. 55, Issue 10
Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumannii
journal, November 2014
- Powers, Rachel A.; Swanson, Hollister C.; Taracila, Magdalena A.
- Biochemistry, Vol. 53, Issue 48
Three Decades of -Lactamase Inhibitors
journal, January 2010
- Drawz, S. M.; Bonomo, R. A.
- Clinical Microbiology Reviews, Vol. 23, Issue 1
β-lactamase inhibitors. The inhibition of serine β-lactamases by specific boronic acids
journal, April 1988
- Crompton, I. E.; Cuthbert, B. K.; Lowe, G.
- Biochemical Journal, Vol. 251, Issue 2
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
- Bou, German; Santillana, Elena; Sheri, Anjaneyulu
- Journal of the American Chemical Society, Vol. 132, Issue 38
Inhibition of a class C beta-lactamase by a specific phosphonate monoester
journal, November 1989
- Pratt, R.
- Science, Vol. 246, Issue 4932
O -Aryloxycarbonyl Hydroxamates: New β-Lactamase Inhibitors That Cross-Link the Active Site
journal, August 2007
- Wyrembak, Pauline N.; Babaoglu, Kerim; Pelto, Ryan B.
- Journal of the American Chemical Society, Vol. 129, Issue 31
Diazabicyclooctanes (DBOs): a potent new class of non-β-lactam β-lactamase inhibitors
journal, October 2011
- Coleman, Ken
- Current Opinion in Microbiology, Vol. 14, Issue 5
Structural and Kinetic Characterization of Diazabicyclooctanes as Dual Inhibitors of Both Serine-β-Lactamases and Penicillin-Binding Proteins
journal, January 2016
- King, Andrew M.; King, Dustin T.; French, Shawn
- ACS Chemical Biology, Vol. 11, Issue 4
Fragment-guided design of subnanomolar -lactamase inhibitors active in vivo
journal, October 2012
- Eidam, O.; Romagnoli, C.; Dalmasso, G.
- Proceedings of the National Academy of Sciences, Vol. 109, Issue 43
Structure-based optimization of cephalothin-analogue boronic acids as β-lactamase inhibitors
journal, February 2008
- Morandi, Stefania; Morandi, Federica; Caselli, Emilia
- Bioorganic & Medicinal Chemistry, Vol. 16, Issue 3
Structural Milestones in the Reaction Pathway of an Amide Hydrolase
journal, March 2002
- Beadle, Beth M.; Trehan, Indi; Focia, Pamela J.
- Structure, Vol. 10, Issue 3
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
- Romagnoli, Chiara; Caselli, Emilia; Prati, Fabio
- European Journal of Organic Chemistry, Vol. 2015, Issue 5
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
- Chaudhari, Sachin Rama; Mogurampelly, Santosh; Suryaprakash, N.
- The Journal of Physical Chemistry B, Vol. 117, Issue 4
Expansion of the σ-hole concept
journal, December 2008
- Murray, Jane S.; Lane, Pat; Politzer, Peter
- Journal of Molecular Modeling, Vol. 15, Issue 6
The origins of the directionality of noncovalent intermolecular interactions #
journal, May 2015
- Wang, Changwei; Guan, Liangyu; Danovich, David
- Journal of Computational Chemistry, Vol. 37, Issue 1
Halogen Interactions in Protein–Ligand Complexes: Implications of Halogen Bonding for Rational Drug Design
journal, November 2013
- Sirimulla, Suman; Bailey, Jake B.; Vegesna, Rahulsimham
- Journal of Chemical Information and Modeling, Vol. 53, Issue 11
Face-to-Face and Edge-to-Face π−π Interactions in a Synthetic DNA Hairpin with a Stilbenediether Linker
journal, September 2003
- Egli, Martin; Tereshko, Valentina; Mushudov, Garib N.
- Journal of the American Chemical Society, Vol. 125, Issue 36
π-Stacking Interactions: ALIVE AND WELL IN PROTEINS
journal, June 1998
- McGaughey, Georgia B.; Gagné, Marc; Rappé, Anthony K.
- Journal of Biological Chemistry, Vol. 273, Issue 25
Effects of Heteroatoms on Aromatic π−π Interactions: Benzene−Pyridine and Pyridine Dimer
journal, February 2009
- Hohenstein, Edward G.; Sherrill, C. David
- The Journal of Physical Chemistry A, Vol. 113, Issue 5
Identification of 50 Class D β-Lactamases and 65 Acinetobacter-Derived Cephalosporinases in Acinetobacter spp.
journal, November 2013
- Périchon, Bruno; Goussard, Sylvie; Walewski, Violaine
- Antimicrobial Agents and Chemotherapy, Vol. 58, Issue 2
Refinement of Macromolecular Structures by the Maximum-Likelihood Method
journal, May 1997
- Murshudov, G. N.; Vagin, A. A.; Dodson, E. J.
- Acta Crystallographica Section D Biological Crystallography, Vol. 53, Issue 3
Phaser crystallographic software
journal, July 2007
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Journal of Applied Crystallography, Vol. 40, Issue 4
Coot model-building tools for molecular graphics
journal, November 2004
- Emsley, Paul; Cowtan, Kevin
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
Functional analyses of AmpC β-lactamase through differential stability
journal, January 1999
- Beadle, Beth M.; Mcgovern, Susan L.; Patera, Alexandra
- Protein Science, Vol. 8, Issue 9
Works referencing / citing this record:
Deciphering the Evolution of Cephalosporin Resistance to Ceftolozane-Tazobactam in Pseudomonas aeruginosa
journal, December 2018
- Barnes, Melissa D.; Taracila, Magdalena A.; Rutter, Joseph D.
- mBio, Vol. 9, Issue 6
Exploring Additional Dimensions of Complexity in Inhibitor Design for Serine β-Lactamases: Mechanistic and Intra- and Inter-molecular Chemistry Approaches
journal, April 2018
- van den Akker, Focco; Bonomo, Robert A.
- Frontiers in Microbiology, Vol. 9
β-lactam/β-lactamase inhibitor combinations: an update
journal, January 2018
- Tehrani, Kamaleddin H. M. E.; Martin, Nathaniel I.
- MedChemComm, Vol. 9, Issue 9
Exploring Additional Dimensions of Complexity in Inhibitor Design for Serine β-Lactamases: Mechanistic and Intra- and Inter-molecular Chemistry Approaches
journal, April 2018
- van den Akker, Focco; Bonomo, Robert A.
- Frontiers in Microbiology, Vol. 9
Structures of FOX-4 Cephamycinase in Complex with Transition-State Analog Inhibitors
journal, April 2020
- Lefurgy, Scott T.; Caselli, Emilia; Taracila, Magdalena A.
- Biomolecules, Vol. 10, Issue 5