Research Report 2010 2011 - Helmholtz-Zentrum für ...

110 SCIENTIFIC REPORTS | Infection and Immunity | Pharmaceutical Research
05.1 Microbial Diversity and Natural Product Discovery
PROJECT LEADER | Prof. Dr. Rolf Müller | Research Group Microbial Drugs | rom@helmholtz-hzi.de
PROJECT MEMBERS | Dr. Klaus Gerth | Dr. Herbert Irschik | Dr. Rolf Jansen | Wolfgang Kessler |
Dr. Kathrin Mohr | Heinrich Steinmetz
Since the closure of the department of natural product
research in 2006, the new group “Microbial Drugs” is focusing
on the discovery and characterization of novel bioactive
compounds from gliding bacteria. Since 2009, it concentrates
on the reactivation, conservation, and screening of our strain
collection.
Elansolid A1
Elansolid A1 and A2
Elansolid A2
Strain collection: For the first time we got a general idea on
the status of the complete strain collection of gliding bacteria
at HZI. We developed strategies how to improve the value of
the collection and at the same time reduce the number of
strains. So far we saved about 700 strains and prepared fresh
culture extracts which were analysed by modern techniques
of HPLC-UV-HRMS. We isolated DNA for genome sequencing
and the search for silent PKS gene clusters and then characterized
the isolates physiologically.
Natural product biology: About 50 strains of myxobacteria
have been isolated from fresh soil samples and screened.
Based on morphology and 16S rDNA analysis, one of these
strains could not be classified to any known group of myxobacteria.
First inhibition tests against different bacteria, yeasts
and fungi revealed a strong unknown antimicrobial and
fungicidal activity. New groups of myxobacteria hold a good
potential for the discovery of new secondary metabolites.
Fermentation: Two major tasks are covered by the fermentation
facility, provision of raw material for structure
elucidation and all other requests from the chemical pipeline
and external partners on one hand and the improvement of
fermentation processes on the other hand.
Basic studies on the improvement of the fermentation process
were done with Chitinophaga Fx GBF13, the producer
of elansolids. The influence of different carbon- and nitrogen
sources, of different pH values of the culture broth and the
effect of oxygen limitations on elansolid A1 production were
studied systematically.
Natural product chemistry: Gephyronic acid was characterized
as a selective inhibitor of eukaryotic protein synthesis
with a nanomolar cytostatic effect against a range
of mammalian cell lines. Using new MS data and chemical
derivatisation the structure was revised and the absolute
configuration of all asymmetric centres was determined.
Parallel fermentations with Fx GBF 13 at different pO 2
. Photo: HZI
1. Jansen, R., Irschik, H., Huch, V., Schummer, D., Steinmetz, H., Bock, M., Schmidt, T.,
Kirschning, A., & Müller, R. (2010) Carolacton -a macrolide ketocarbonic acid reducing
biofilm by the caries- and endocarditis-associated bacterium Streptococcus mutans.
European Journal of Organic Chemistry 7, 1284.
Development of an anhydrous isolation procedure for a novel
elansolid A isomer surprisingly revealed a common precursor
of the atropisomers elansolids A1 and A2. Genetic studies
now are expected to show which elansolid A isomer really
represents the final product of the biosynthesis.
2. Buntin, K., Irschik, H., Weissman, K. J., Luxenburger, E., Blöcker, H., & Müller, R.
(2010) Biosynthesis of Thuggacins in Myxobacteria: Comparative cluster analysis
reveals basis for natural product structural diversity. Chemistry & Biology 17, 342.
3. Irschik, H., Kopp, M., Weissman, K. J., Buntin, K., Piel, J., & Müller, R. (2010) Analysis
of the sorangicin gene cluster reinforces the utitlity of a combined hylogenetic/
retrobiosynthetic analysis for deciphering natural product assembly by transATPKS.
ChemBioChem 11, 1840.
4. Nawrath, T., Gerth, K., Müller, R., & Schulz, S. (2010) The biosynthesis of the aroma
volatile 2-methyltetrahydrothiophen-3-one in the bacterium Chitinophaga Fx 7914.
ChemBioChem 11, 1014.
5. Menche, D., & Irschik, H. (2010). Design, synthesis and biological evaluation of simplified
analogues of the RNA polymerase inhibitor etnangien. Bioorganic & Medicinal
Chemistry Letters 20, 939.
6. Bü low, L ., Nickeleit, I., Gi rbig, A .- K ., Brod ma n n, T., Rentsch, A ., Egger t, U., Sasse,
F., Steinmetz, H., Frank, R., Carlomagno, T., Malek, N.P., & Kalesse, M. (2010).Synthesis
and biological characterization of argyrin F. ChemMedChem 5, 832.