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• W2071055168 abstract "Class D β-lactamases represent a growing and diverse class of penicillin-inactivating enzymes that are usually resistant to commercial β-lactamase inhibitors. As many such enzymes are found in multi-drug resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa, novel β-lactamase inhibitors are urgently needed. Five unique 6-alkylidene-2′-substituted penicillanic acid sulfones (1−5) were synthesized and tested against OXA-24, a clinically important β-lactamase that inactivates carbapenems and is found in A. baumannii. Based upon the roles Tyr112 and Met223 play in the OXA-24 β-lactamase, we also engineered two variants (Tyr112Ala and Tyr112Ala,Met223Ala) to test the hypothesis that the hydrophobic tunnel formed by these residues influences inhibitor recognition. IC50 values against OXA-24 and two OXA-24 β-lactamase variants ranged from 10 ± 1 (4 vs WT) to 338 ± 20 nM (5 vs Tyr112Ala, Met223Ala). Compound 4 possessed the lowest Ki (500 ± 80 nM vs WT), and 1 possessed the highest inactivation efficiency (kinact/Ki = 0.21 ± 0.02 μM−1 s−1). Electrospray ionization mass spectrometry revealed a single covalent adduct, suggesting the formation of an acyl-enzyme intermediate. X-ray structures of OXA-24 complexed to four inhibitors (2.0−2.6 Å) reveal the formation of stable bicyclic aromatic intermediates with their carbonyl oxygen in the oxyanion hole. These data provide the first structural evidence that 6-alkylidene-2′-substituted penicillin sulfones are effective mechanism-based inactivators of class D β-lactamases. Their unique chemistry makes them developmental candidates. Mechanisms for class D hydrolysis and inhibition are discussed, and a pathway for the evolution of the BlaR1 sensor of Staphylococcus aureus to the class D β-lactamases is proposed." @default.
• W2071055168 created "2016-06-24" @default.
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• W2071055168 date "2010-09-07" @default.
• W2071055168 modified "2023-10-08" @default.
• W2071055168 title "Design, Synthesis, and Crystal Structures of 6-Alkylidene-2′-Substituted Penicillanic Acid Sulfones as Potent Inhibitors of <i>Acinetobacter baumannii</i> OXA-24 Carbapenemase" @default.
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• W2071055168 doi "https://doi.org/10.1021/ja104092z" @default.
• W2071055168 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3393087" @default.
• W2071055168 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/20822105" @default.
• W2071055168 hasPublicationYear "2010" @default.
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