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X-ray crystal structure of ADC-33 in complex with sulfonamidoboronic acid 6dX-ray crystal structure of ADC-33 in complex with sulfonamidoboronic acid 6d
Structural highlights
FunctionPublication Abstract from PubMedAcinetobacter 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 beta-lactams. One of the most important mechanisms is the production of beta-lactamase enzymes capable of hydrolyzing beta-lactam antibiotics. Co-expression of multiple classes of beta-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 beta-lactamase inhibitors, we previously identified a sulfonamidomethaneboronic acid CR167 active against Acinetobacter-derived class C beta-lactamases (ADC-7). The compound demonstrated affinity for ADC-7 with a K(i) = 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 beta-lactamases in A. baumannii: the cefepime-hydrolysing class C extended-spectrum beta-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. 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.,Introvigne ML, Beardsley TJ, Fernando MC, Leonard DA, Wallar BJ, Rudin SD, Taracila MA, Rather PN, Colquhoun JM, Song S, Fini F, Hujer KM, Hujer AM, Prati F, Powers RA, Bonomo RA, Caselli E Antibiotics (Basel). 2023 Mar 24;12(4):644. doi: 10.3390/antibiotics12040644. PMID:37107006[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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