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Sulfonamidoboronic Acids as “Cross-Class” Inhibitors of an Expanded-Spectrum Class C Cephalosporinase, ADC-33, and a Class D Carbapenemase, OXA-24/40: Strategic Compound Design to Combat Resistance in Acinetobacter baumannii

Journal Article · · Antibiotics
 [1];  [2];  [2];  [2];  [2];  [3];  [3];  [4];  [5];  [6];  [1];  [3];  [3];  [1];  [2];  [7];  [1]
  1. Università di Modena e Reggio Emilia (Italy)
  2. Grand Valley State University, Allendale, MI (United States)
  3. Case Western Reserve Univ., Cleveland, OH (United States). School of Medicine; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH (United States)
  4. Atlanta Veterans Medical Center, Decatur, GA (United States); Emory Univ., Atlanta, GA (United States). School of Medicine
  5. Emory Univ., Atlanta, GA (United States). School of Medicine
  6. Atlanta Veterans Medical Center, Decatur, GA (United States)
  7. Case Western Reserve Univ., Cleveland, OH (United States). School of Medicine; Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH (United States). Center for Antimicrobial Resistance and Epidemiology (CARES)
+ Show Author Affiliations
Acinetobacter baumannii is a Gram-negative organism listed as an urgent threat pathogen by the World Health Organization (WHO). Carbapenem-resistant A. baumannii (CRAB), especially, present therapeutic challenges due to complex mechanisms of resistance to β-lactams. One of the most important mechanisms is the production of β-lactamase enzymes capable of hydrolyzing β-lactam antibiotics. Co-expression of multiple classes of β-lactamases is present in CRAB; therefore, the design and synthesis of “cross-class” inhibitors is an important strategy to preserve the efficacy of currently available antibiotics. To identify new, nonclassical β-lactamase inhibitors, we previously identified a sulfonamidomethaneboronic acid CR167 active against Acinetobacter-derived class C β-lactamases (ADC-7). The compound demonstrated affinity for ADC-7 with a Ki = 160 nM and proved to be able to decrease MIC values of ceftazidime and cefotaxime in different bacterial strains. Herein, we describe the activity of CR167 against other β-lactamases in A. baumannii: the cefepime-hydrolysing class C extended-spectrum β-lactamase (ESAC) ADC-33 and the carbapenem-hydrolyzing OXA-24/40 (class D). These investigations demonstrate CR167 as a valuable cross-class (C and D) inhibitor, and the paper describes our attempts to further improve its activity. Five chiral analogues of CR167 were rationally designed and synthesized. The structures of OXA-24/40 and ADC-33 in complex with CR167 and select chiral analogues were obtained. The structure activity relationships (SARs) are highlighted, offering insights into the main determinants for cross-class C/D inhibitors and impetus for novel drug design.
Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
2423670
Journal Information:
Antibiotics, Journal Name: Antibiotics Journal Issue: 4 Vol. 12; ISSN 2079-6382
Publisher:
MDPICopyright Statement
Country of Publication:
United States
Language:
English

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Figures / Tables (13)

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Table 1(p. 5)table Table 1
Table 2(p. 5)table Table 2
Figure 3(p. 7)figure Figure 3
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Figure 5(p. 8)figure Figure 5
Scheme 1(p. 9)figure Scheme 1
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Table 3(p. 11)table Table 3
Table 4(p. 12)table Table 4
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60 APPLIED LIFE SCIENCES
Acinetobacter baumannii
Infectious Diseases
Pharmacology & Pharmacy
antibiotic resistance
boronic acids
cross-class inhibitors
β-lactamases