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Title: 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:
 [1];  [1];  [1];  [1];  [2];  [3];  [3];  [3]; ORCiD logo [2]; ORCiD logo [1];  [1]
  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)
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}
}

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Works referencing / citing this record:

Deciphering the Evolution of Cephalosporin Resistance to Ceftolozane-Tazobactam in Pseudomonas aeruginosa
journal, December 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