Adduct Formation and Context Factors in Drug Hypersensitivity: Insight from Proteomic Studies

González-Morena, Juan M.; Montanez, Maria I.; Aldini, Giancarlo; Sánchez‐Gómez, Francisco J.

doi:10.2174/1381612822666160927113748

Cited by 11 publications

(15 citation statements)

References 85 publications

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“…Therefore, oxidative stress is a concomitant factor in numerous pathological situations requiring antibiotic administration. Oxidative stress can influence drug protein-adduct formation by multiple mechanisms, including induction of conformational alterations or oxidative modifications that can either increase or blunt the reactivity of the modified residues towards the drug, as we have recently reviewed (González-Morena et al, 2016). While exploring the impact of oxidants or reducing agents on protein modification by AX, we observed that the presence of exogenous thiol-containing molecules influenced the extent of AX-protein adduct formation.…”

Section: Introductionmentioning

confidence: 86%

Amoxicillin Inactivation by Thiol-Catalyzed Cyclization Reduces Protein Haptenation and Antibacterial Potency

et al. 2020

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Serum and cellular proteins are targets for the formation of adducts with the b-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 b-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.

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Section: Introductionmentioning

confidence: 86%

Amoxicillin Inactivation by Thiol-Catalyzed Cyclization Reduces Protein Haptenation and Antibacterial Potency

et al. 2020

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“…Human serum albumin (HSA) can be considered the main protein target for haptenation by β‐lactams, since it is the most abundant protein in plasma, has multiple binding sites, and acts as a carrier for endogenous and exogenous compounds . To gain insight into the haptenation process, proteomic studies with HSA have been performed with different β‐lactams . Conjugation of these antibiotics is mainly driven by the nucleophilic attack of lysine amino groups from the protein to the electrophilic carbonyl group of the β‐lactam ring .…”

Section: Introductionmentioning

confidence: 99%

Identification of an antigenic determinant of clavulanic acid responsible for IgE‐mediated reactions

Barbero

Mayorga

Martín-Serrano

et al. 2019

Allergy

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Background: Selective reactions to clavulanic acid (CLV) account for around 30% of immediate reactions after administration of amoxicillin-CLV. Currently, no immunoassay is available for detecting specific IgE to CLV, and its specific recognition in patients with immediate reactions has only been demonstrated by basophil activation testing, however with suboptimal sensitivity. The lack of knowledge regarding the structure of the drug that remains bound to proteins (antigenic determinant) is hampering the development of in vitro diagnostics. We aimed to identify the antigenic determinants of CLV as well as to evaluate their specific IgE recognition and potential role for diagnosis.Methods: Based on complex CLV degradation mechanisms, we hypothesized the formation of two antigenic determinants for CLV, AD-I (N-protein, 3-oxopropanamide) and AD-II (N-protein, 3-aminopropanamide), and designed different synthetic analogs to each one. IgE recognition of these structures was evaluated in basophils from patients with selective reactions to CLV and tolerant subjects. In parallel, the CLV fragments bound to proteins were identified by proteomic approaches.Results: Two synthetic analogs of AD-I were found to activate basophils from allergic patients. This determinant was also detected bound to lysines 195 and 475 of CLVtreated human serum albumin. One of these analogs was able to activate basophils in 59% of patients whereas CLV only in 41%. Combining both results led to an increase in basophil activation in 69% of patients, and only in 12% of controls.

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“…Therefore, AX reactivity and conjugation to carrier molecules have been the subject of thorough investigation [15,25]. The redox status is a major determinant of drug action and oxidative stress is a well-recognized coadjuvant factor in drug adverse reactions [14]. Moreover, the redox status and oxidative modifications can influence drug binding to carrier proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, oxidative stress is a concomitant factor in numerous pathological situations requiring antibiotic administration. Oxidative stress can influence drug protein-adduct formation by multiple mechanisms, including induction of conformational alterations or oxidative modifications that can either increase or blunt the reactivity of the modified residues towards the drug, as we have recently reviewed [14]. While exploring the impact of oxidative or reducing agents on protein modification by AX, we observed that the presence of exogenous thiol-containing molecules influenced the extent of AX-protein adduct formation.…”

Section: Introductionmentioning

confidence: 86%

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Amoxicillin inactivation by thiol-catalyzed cyclization reduces protein haptenation and antibacterial potency

Pajares

Zimmerman

Sánchez‐Gómez

et al. 2019

Preprint

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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 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. 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.Recent work of our group identified several serum proteins as potential targets for haptenation by amoxicillin (AX) [8]. In addition, intracellular proteins are also susceptible of covalent modification by this antibiotic [9,10]. Nucleophilicity and a favorable environment appear to be important for the selective modification of proteins on certain residues. In vitro, incubation of human serum albumin (HSA) with AX, results in the modification of several lysine residues of which, Lys190 and Lys195 appear to be the most reactive [8]. Interestingly, after oral administration of AX, only modified Lys190 has been found [11,12]. Apart from the chemical reactivity of the antibiotic and the protein residues, little is known about other factors influencing protein haptenation by AX in biological settings.Previous studies with the antibiotic sulfamethoxazole have shown that oxidative stress can potentiate the formation of protein adducts in cells [13]. This alteration of the redox status

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Adduct Formation and Context Factors in Drug Hypersensitivity: Insight from Proteomic Studies

Cited by 11 publications

References 85 publications

Amoxicillin Inactivation by Thiol-Catalyzed Cyclization Reduces Protein Haptenation and Antibacterial Potency

Amoxicillin Inactivation by Thiol-Catalyzed Cyclization Reduces Protein Haptenation and Antibacterial Potency

Identification of an antigenic determinant of clavulanic acid responsible for IgE‐mediated reactions

Amoxicillin inactivation by thiol-catalyzed cyclization reduces protein haptenation and antibacterial potency

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