Bioactive Agents from Natural Sources: Trends in Discovery and Application - Advances in Biochemical Engineering Biotechnology - page 102

tive inhibitor of glutamine synthetase bearing only low toxicity [5]. The
antibacterial tripeptide L -phosphinothricyl- L -alanyl- L -alanine (bialaphos)
can be isolated from culture broths of Streptomyces viridochromogenes [6],
and Streptomyces hygroscopicus [7].Antibiotic resistance of the producing
organism is due to enzymatic N -acetylation ofa biosynthetic tripeptide pre-
cursor [8].To broaden the application range of phosphinothricin as a her-
bicide the gene for the corresponding N -acetyltransferase was successfully
transferred to plants in order to generate Basta resistant transgenic crops
[9].Basta was commercialized by the German company Hoechst as a race-
mate derived from chemical synthesis.
ii) The avermectins isolated from Streptomyces avermitilis exhibit broad insec-
ticidal, ascaricidal, and antihelmintic activity even at very low concentra-
tions without showing any antibacterial or antifungal activity. They were
discovered by using an animal model to detect anticoccidial agents [10].
Detailed studies proved that the avermectins interact in a unique manner
with the GABA regulated chloride ion channels.Chemical modification of
the macrolide type avermectins resulted in ivermectin which was commer-
cialized as a mixture ofivermectin B 1a and B 1b by the US company Merck for
application in agriculture and animal health care,as well as in human medi-
cine to prevent river blindness in the developing countries of Africa and
Central America [11].
iii) Most recently,representatives of a completely new class of non-phytotoxic
agro-fungicides were successfully brought onto the market by the German
company BASF and the English company ICI.The compounds were devel-
oped by total synthesis starting from the fungal metabolites strobilurin and
oudemansin discovered by T.Anke and W. Steglich as lead structures [12,
13].Antifungal activity was proven to be due to the inhibition of the mito-
chondrial bc 1 complex of the fungal respiratorial chain.Toxicity is prevent-
ed by rapid metabolic processes in mammals and numerous other eukaryo-
tic organisms.
1.2
High-Throughput Screening Towards Lead Discovery
Breakthroughs in molecular biology,cell biology,and genetic engineering in the
1980s gave rise to understanding diseases on the molecular or on the gene level.
Subsequently, constructing novel target directed screening systems of pro-
mising therapeutic significance resulted in changing industrial drug discovery
attempts completely [3,4,14].Thus,during the last few years a large number of
different molecular screening assays has been developed. Transfer to the 96-
well or, more recently, to the 384-well microplate format, automation and
miniaturization turned out to be crucial with respect to industrial high-
throughput screening (HTS).Down-scaling of the assay volume to the 1,536-
well format is already underway, although considerable problems have to be
solved mainly concerning liquid-handling in the nanoliter range and assay
read-out.However,approaches towards the testing of 100,000 samples per day
are in progress.