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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:
Michigan Economic Development Corporation; Michigan Technology Tri-Corridor; National Inst. of Allergy and Infectious Diseases of the National Inst. of Health; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Scientific User Facilities Division
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1431376
Journal Information:
ACS Infectious Diseases, Journal Name: ACS Infectious Diseases Journal Issue: 3 Vol. 4; ISSN 2373-8227
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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

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