Interactions of hydrolyzed β-lactams with the L1 metallo-β-lactamase: Crystallography supports stereoselective binding of cephem/carbapenem products.
L1 carbapenemase
X-ray crystallography
antibiotic resistance
carbapenem
hydrolysis
metallo β-lactamase
β-lactam
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
05 2023
05 2023
Historique:
received:
05
10
2022
revised:
25
02
2023
accepted:
27
02
2023
medline:
29
5
2023
pubmed:
17
3
2023
entrez:
16
3
2023
Statut:
ppublish
Résumé
L1 is a dizinc subclass B3 metallo-β-lactamase (MBL) that hydrolyzes most β-lactam antibiotics and is a key resistance determinant in the Gram-negative pathogen Stenotrophomonas maltophilia, an important cause of nosocomial infections in immunocompromised patients. L1 is not usefully inhibited by MBL inhibitors in clinical trials, underlying the need for further studies on L1 structure and mechanism. We describe kinetic studies and crystal structures of L1 in complex with hydrolyzed β-lactams from the penam (mecillinam), cephem (cefoxitin/cefmetazole), and carbapenem (tebipenem, doripenem, and panipenem) classes. Despite differences in their structures, all the β-lactam-derived products hydrogen bond to Tyr33, Ser221, and Ser225 and are stabilized by interactions with a conserved hydrophobic pocket. The carbapenem products were modeled as Δ
Identifiants
pubmed: 36924941
pii: S0021-9258(23)00248-X
doi: 10.1016/j.jbc.2023.104606
pmc: PMC10148155
pii:
doi:
Substances chimiques
Anti-Bacterial Agents
0
beta-Lactamase Inhibitors
0
beta-lactamase L1
EC 3.5.2.-
beta-Lactamases
EC 3.5.2.6
beta-Lactams
0
Carbapenems
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
104606Subventions
Organisme : NIAID NIH HHS
ID : R01 AI100560
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI123835
Pays : United States
Organisme : Biotechnology and Biological Sciences Research Council
Pays : United Kingdom
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.