RT Journal Article
T1 Amoxicillin Inactivation by Thiol-Catalyzed Cyclization Reduces Protein Haptenation and Antibacterial Potency.
A1 Pajares, Maria A
A1 Zimmerman, Tahl
A1 Sanchez-Gomez, Francisco J
A1 Ariza, Adriana
A1 Torres, Maria J
A1 Blanca, Miguel
A1 Cañada, F Javier
A1 Montañez, Maria I
A1 Perez-Sala, Dolores
K1 Amoxicillin
K1 Bacterial growth
K1 Inactivation mechanism
K1 Protein adducts
K1 Redox regulation
K1 Thiol groups
K1 Thiol-containing molecules
K1 β-lactam antibiotics
AB Serum and cellular proteins are targets for the formation of adducts with the β-lactam antibiotic amoxicillin. This process could be important for the development of adverse, and in particular, allergic reactions to this antibiotic. In studies exploring protein haptenation by amoxicillin, we observed that reducing agents influenced the extent of amoxicillin-protein adducts formation. Consequently, we show that several thiol-containing compounds, including dithiothreitol, N-acetyl-L-cysteine, and glutathione, perform a nucleophilic attack on the amoxicillin molecule that is followed by an internal rearrangement leading to amoxicillin diketopiperazine, a known amoxicillin metabolite with residual activity. Increased diketopiperazine conversion is also observed with human serum albumin but not with L-cysteine, which mainly forms the amoxicilloyl amide. The effect of thiols is catalytic and can render complete amoxicillin conversion. Interestingly, this process is dependent on the presence of an amino group in the antibiotic lateral chain, as in amoxicillin and ampicillin. Furthermore, it does not occur for other β-lactam antibiotics, including cefaclor or benzylpenicillin. Biological consequences of thiol-mediated amoxicillin transformation are exemplified by a reduced bacteriostatic action and a lower capacity of thiol-treated amoxicillin to form protein adducts. Finally, modulation of the intracellular redox status through inhibition of glutathione synthesis influenced the extent of amoxicillin adduct formation with cellular proteins. These results open novel perspectives for the understanding of amoxicillin metabolism and actions, including the formation of adducts involved in allergic reactions.
PB Frontiers Research Foundation
SN 1663-9812
YR 2020
FD 2020-03-04
LK https://hdl.handle.net/10668/26837
UL https://hdl.handle.net/10668/26837
LA en
NO Pajares MA, Zimmerman T, Sánchez-Gómez FJ, Ariza A, Torres MJ, Blanca M, et al. Amoxicillin Inactivation by Thiol-Catalyzed Cyclization Reduces Protein Haptenation and Antibacterial Potency. Front Pharmacol. 2020 Mar 4;11:189
NO This work was supported by grant SAF2015-68590-R from MINECO/FEDER, RTI2018-097624-B-I00 and RETIC Aradyal from ISCIII/FEDER RD16/0006/0021 to DP-S; RD16/0006/0001 to MT, RD16/0006/0024 to MB; grants CP15/00103 and PI17/01237 from ISCIII/ERDF and PI-0179-2014 from Andalusian Regional Ministry Health to MM. AA holds a “Sara Borrell” research contract (CD17/0146) supported by ISCIII from MINECO [cofunded by the European Social Fund (ESF)]. We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).
DS RISalud
RD Apr 10, 2025