RESUMO
We present the first synthesis of ß-lactam-derived haptens, leveraging the principles of diversity-oriented synthesis to discover compounds for drug allergy in vitro testing. We designed, synthesised, and performed in vitro immunological evaluation on 18 structurally diverse haptens derived from ß-lactam antibiotics. The antigens obtained with the synthesised haptens allow for the detection of specific anti-ß-lactam immunoglobulins G and E. Excellent diagnostic sensitivity (83%) and specificity (100%) were achieved when the panel of antigens was tested against a cohort of 31 human serum samples using a multiplexed compact disc-based in vitro testing tool. We posit that adopting this strategy could aid ß-lactam delabeling initiatives.
Assuntos
Hipersensibilidade a Drogas , beta-Lactamas , Antibacterianos/farmacologia , Estudos de Coortes , Hipersensibilidade a Drogas/diagnóstico , Haptenos , Humanos , Imunoglobulina ERESUMO
The synthesis of structurally new haptens and the development of suitable antigens are essential for boosting the sensitivity of drug allergy diagnostic testing. Unprecedented structural antigens for benzylpenicillin and amoxicillin are characterised and evaluated in a cohort of 70 subjects with a turnkey solution based on consumer electronics.
Assuntos
Testes Diagnósticos de Rotina/métodos , Hipersensibilidade a Drogas/metabolismo , Haptenos/química , Lactamas/metabolismo , beta-Lactamas/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Amoxicilina/química , Antibacterianos/química , Aztreonam/química , Carbonatos/química , Estudos de Coortes , Diaminas/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Penicilina G/química , Albumina Sérica Humana/química , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
New antigens deriving from -lloyl and -llanyl, major and minor determinants, respectively, were produced for ß-lactam antibiotics cefuroxime, cefotaxime, ceftriaxone, meropenem and aztreonam. Twenty ß-lactam antigens were produced using human serum albumin and histone H1 as carrier proteins. Antigens were tested by multiplex in vitro immunoassays and evaluated based on the detection of specific IgG and IgE in the serum samples. Both major and minor determinants were appropriate antigens for detecting specific anti-ß-lactam IgG in immunised rabbit sera. In a cohort of 37 allergic patients, we observed that only the minor determinants (-llanyl antigens) were suitable for determining specific anti-ß-lactam IgE antibodies with high sensitivity (< 0.01 IU/mL; 24 ng/L) and specificity (100%). These findings reveal that not only the haptenisation of ß-lactam antibiotics renders improved molecular recognition events when the 4-member ß-lactam ring remains unmodified, but also may contribute to develop promising minor antigens suitable for detecting specific IgE-mediated allergic reactions. This will facilitate the development of sensitive and selective multiplexed in vitro tests for drug-allergy diagnoses to antibiotics cephalosporin, carbapenem and monobactam.
