8CUP

X-ray crystal structure of ADC-33 in complex with sulfonamidoboronic acid 6d

Summary for 8CUP

• Entry DOI: 10.2210/pdb8cup/pdb
• Descriptor: Beta-lactamase, 3-[(4S)-4-ethyl-5,7,7-trihydroxy-2,2,7-trioxo-6-oxa-2lambda~6~-thia-3-aza-7lambda~5~-phospha-5-boraheptan-1-yl]benzoic acid (3 entities in total)
• Functional Keywords: cephalasporinase, inhibitor, hydrolase, hydrolase-inhibitor complex, hydrolase/inhibitor
• Biological source: Acinetobacter baumannii
• Total number of polymer chains: 2
• Total formula weight: 82391.31

Authors

Fernando, M.C.,Wallar, B.J.,Powers, R.A. (deposition date: 2022-05-17, release date: 2023-04-05, Last modification date: 2024-11-06)

Primary citation

Introvigne, M.L.,Beardsley, T.J.,Fernando, M.C.,Leonard, D.A.,Wallar, B.J.,Rudin, S.D.,Taracila, M.A.,Rather, P.N.,Colquhoun, J.M.,Song, S.,Fini, F.,Hujer, K.M.,Hujer, A.M.,Prati, F.,Powers, R.A.,Bonomo, R.A.,Caselli, E.
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 .
Antibiotics, 12:-, 2023

PubMed Abstract: is a Gram-negative organism listed as an urgent threat pathogen by the World Health Organization (WHO). Carbapenem-resistant (CRAB), especially, present therapeutic challenges due to complex mechanisms of resistance to -lactams. One of the most important mechanisms is the production of -lactamase enzymes capable of hydrolyzing -lactam antibiotics. Co-expression of multiple classes of -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 -lactamase inhibitors, we previously identified a sulfonamidomethaneboronic acid active against -derived class C -lactamases (ADC-7). The compound demonstrated affinity for ADC-7 with a = 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 against other -lactamases in : the cefepime-hydrolysing class C extended-spectrum -lactamase (ESAC) ADC-33 and the carbapenem-hydrolyzing OXA-24/40 (class D). These investigations demonstrate as a valuable cross-class (C and D) inhibitor, and the paper describes our attempts to further improve its activity. Five chiral analogues of were rationally designed and synthesized. The structures of OXA-24/40 and ADC-33 in complex with 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.

PubMed: 37107006
DOI: 10.3390/antibiotics12040644

Experimental method

X-RAY DIFFRACTION (1.54 Å)