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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 .
- Source :
-
Antibiotics (Basel, Switzerland) [Antibiotics (Basel)] 2023 Mar 24; Vol. 12 (4). Date of Electronic Publication: 2023 Mar 24. - Publication Year :
- 2023
-
Abstract
- 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 K <subscript>i</subscript> = 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.
Details
- Language :
- English
- ISSN :
- 2079-6382
- Volume :
- 12
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Antibiotics (Basel, Switzerland)
- Publication Type :
- Academic Journal
- Accession number :
- 37107006
- Full Text :
- https://doi.org/10.3390/antibiotics12040644