Abstract
ACC-1 is a plasmid-encoded class C β-lactamase identified in clinical isolates of Klebsiella pneumoniae, Proteus mirabilis, Salmonella enterica, and Escherichia coli. ACC-1-producing bacteria are susceptible to cefoxitin, whereas they are resistant to oxyimino cephalosporins. Here, we depict crystal structures of apo ACC-1, adenylylated ACC-1, and acylated ACC-1 complexed with cefotaxime and cefoxitin. ACC-1 has noteworthy structural alterations in the R2 loop, the Ω loop, and the Phe119 loop located along the active-site rim. The adenylate covalently bonded to the nucleophilic serine reveals a tetrahedral phosphorus mimicking the deacylation transition state. Cefotaxime in ACC-1 has a proper conformation for the substrate-assisted catalysis in that its C-4 carboxylate and N-5 nitrogen are adequately located to facilitate the deacylation reaction. In contrast, cefoxitin in ACC-1 has a distinct conformation, in which those functional groups cannot contribute to catalysis. Furthermore, the orientation of the deacylating water relative to the acyl carbonyl group in ACC-1 is unfavorable for nucleophilic attack.
Original language | English |
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Article number | e0141119 |
Journal | Antimicrobial Agents and Chemotherapy |
Volume | 63 |
Issue number | 11 |
DOIs | |
State | Published - 2019 |
Bibliographical note
Publisher Copyright:Copyright © 2019 American Society for Microbiology. All Rights Reserved.
Keywords
- ACC-1 class C β-lactamase
- Acyl-enzyme complex
- Adenylylation
- Cefotaxime
- Cefoxitin
- Crystal structures