Shared Clavulanate and Tazobactam Antigenic Determinants Activate T-Cells from Hypersensitive Patients
Issued Date
2022-11-21
Resource Type
ISSN
0893228X
eISSN
15205010
Scopus ID
2-s2.0-85139174748
Pubmed ID
36137197
Journal Title
Chemical Research in Toxicology
Volume
35
Issue
11
Start Page
2122
End Page
2132
Rights Holder(s)
SCOPUS
Bibliographic Citation
Chemical Research in Toxicology Vol.35 No.11 (2022) , 2122-2132
Suggested Citation
Ariza A., Jaruthamsophon K., Meng X., Labella M., Adair K., Tailor A., Sukasem C., Whitaker P., Peckham D., Pirmohamed M., Torres M.J., Naisbitt D.J. Shared Clavulanate and Tazobactam Antigenic Determinants Activate T-Cells from Hypersensitive Patients. Chemical Research in Toxicology Vol.35 No.11 (2022) , 2122-2132. 2132. doi:10.1021/acs.chemrestox.2c00231 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/86822
Title
Shared Clavulanate and Tazobactam Antigenic Determinants Activate T-Cells from Hypersensitive Patients
Other Contributor(s)
Abstract
β-Lactamase inhibitors such as clavulanic acid and tazobactam were developed to overcome β-lactam antibiotic resistance. Hypersensitivity reactions to these drugs have not been studied in detail, and the antigenic determinants that activate T-cells have not been defined. The objectives of this study were to (i) characterize clavulanate- and tazobactam-responsive T-cells from hypersensitive patients, (ii) explore clavulanate and tazobactam T-cell crossreactivity, and (iii) define the antigenic determinants that contribute to T-cell reactivity. Antigen specificity, pathways of T-cell activation, and crossreactivity with clavulanate- and tazobactam-specific T-cell clones were assessed by proliferation and cytokine release assays. Antigenic determinants were analyzed by mass spectrometry-based proteomics methods. Clavulanate- and tazobactam-responsive CD4+T-cell clones were stimulated to proliferate and secrete IFN-γin an MHC class II-restricted and dose-dependent manner. T-cell activation with clavulanate- and tazobactam was dependent on antigen presenting cells because their fixation prevented the T-cell response. Strong crossreactivity was observed between clavulanate- and tazobactam-T-cells; however, neither drug activated β-lactam antibiotic-responsive T-cells. Mass spectrometric analysis revealed that both compounds form multiple antigenic determinants with lysine residues on proteins, including an overlapping aldehyde and hydrated aldehyde adduct with mass additions of 70 and 88 Da, respectively. Collectively, these data show that although clavulanate and tazobactam are structurally distinct, the antigenic determinants formed by both drugs overlap, which explains the observed T-cell cross-reactivity.