Bioactive Agents from Natural Sources: Trends in Discovery and Application - Advances in Biochemical Engineering Biotechnology - page 106

mentin [20, 22]. Regarding the hit-list of antibacterials, the only competitive
synthetics to the -lactams,so far,are the quinolone carboxylic acids affecting

the bacterial topoisomerase (DNA gyrase) [23].The top-selling drug ciprofloxa-
cin was introduced under the trade name of Ciprobay by Bayer in 1986.
Further antibiotics,mainly derived from actinomycetes,are used for special
applications in human and veterinary medicine [20]. These compounds have
numerous chemical structures.The macrolides,tetracyclines,aminoglycosides,
glycopeptides,and ansamycins for instance are used in antibacterial treatment
whereas the anthracyclines reached the market to supplement anticancer
chemotherapy.The fairly toxic polyether-type antibiotics are preferably used as
anticoccidial agents. Due to the dramatically increasing resistance of clinical
important bacterial strains new targets for the discovery of novel types of anti-
bacterial agents are urgently needed.

b

2.2
Immunosuppressant Drugs

The cyclic peptide cyclosporin A was identified at Sandoz in Switzerland as an
antifungal agent isolated from culture broths of the fungus Tolypocladium in-
flatum ,former classified as Trichoderma polysporum [24].In the course ofmore
detailed pharmacological studies applying improved in vivo animal models
cyclosporin A performed remarkable immunosuppressive properties [25, 26].
As a result of its superior efficiency,cyclosporin A was commercialized under
the trade name Sandimmune only seven years after it had been first reported.
For the first time, transplantation surgery was provided with a drug that pre-
vented organ rejection effectively without substantially affecting the immune
response giving protection against bacterial infections. Considering that pa-
tients of successful transplantation surgeries have to take cyclosporin A for the
rest of their life this issue is of great importance.Cyclosporin A is still in the top
twentyfive drugs worldwide,although it was introduced as early as 1983.How-
ever,in spite of great efforts made by Sandoz and numerous competitors to de-
velop an improved immunosuppressant, cyclosporin A, is still in the number
one position in immunosuppressive drug sales [27].
Studies on the mode of action of cyclosporin A revealed interaction with
intracellular signal transduction pathways leading to the inhibition of inter-
leukin-2 production in T-cell cultures. Subsequent screening for inhibitors of
interleukin-2 release at Fujisawa in Japan resulted in the discovery of the
macrocyclic lactame FK 506 from the culture broth of Streptomyces tsukubaen-
sis in 1984 [28,29].Structural similarities to rapamycin,previously described as
an antifungal metabolite from Streptomyces hygroscopicus [30],gave rise for the
reevaluation of the biological activities of rapamycin. Detailed studies on the
mechanism of action of rapamycin, FK 506, and cyclosporin A yielded com-
pletely new insights into eukaryotic cell signaling,and led to the discovery of a
new and unusual class of proteins called immunophilins.Although FK 506 and
rapamycin bind to the same protein,called FK binding protein (FKBP),the com-
plexes formed trigger different signaling pathways. In T-cell cultures the FK
506/FKBP complex binds to calcineurin thus preventing its interaction with