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
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.