QSAR study of immunotoxicity in antibiotics
Since their inception the B-Iactam antibiotics have become one of the most important classes of phannaceutical agents, both therapeutically and economically, in modern day usage for the treatment of a wide spectrum of bacterial infections. However, due to the versatility of bacteria many previously treatable species are developing resistance to the antibiotics currently available and so there is ever a need to develop more ~-lactam antibiotics, which are effective and yet safe. A major drawback to the ~-lactams is the degree of immunologically adverse reactions they induce. It was the aim of this study to develop both mechanistic and immunological methods to enable the prediction of a B-lactam's potential to induce an allergic response and to determine if a relationship between these responses and the molecular properties of the ~-lactams was present. In this study a database pertaining to frequency by which 70 p-lactams induce adverse reactions has been compiled and used to produce 27 QSAR models. A highly sensitive assay for the quantitation of cross-reactivity between B-lactams and serum anti-benzylpenicillin antibodies has been developed and used to determine the cross-reactivity potential of 31 ~-lactams and to develop 18 QSAR models. All of the QSARs developed suggest that the shape and electron separation of the ~-lactams are crucial to the development and extent of adverse response or crossreactivity induced by a specific p-lactam antibiotic, new or old. The QSARs developed will enable the design and development of new ~-lactam antibiotics which present a significantly lower risk of inducing immunologically mediated adverse responses when used therapeutically. Two sensitive assays for the quantitative detennination of the cytokines IL2 and IL4 in lymphocyte culture supernatants have been developed, and have been shown to have a potential use in the prediction of the type of immunological response initiated following p-Iactam stimulation of a sensitised individual.