Research in the Müller group
addresses the chemistry, biosynthesis, regulation, heterologous production and
mode-of-action of secondary metabolites from myxobacteria and, more recently,
Natural products (secondary metabolites) derived from microbes, plants and fungi, form the bedrock of the modern pharmaceutical industry. Among other activities, these compounds act as antibiotics (e.g. erythromycin,tetracycline), anti-cancer drugs (mitomycin, epothilone), cholesterol-lowering
agents (lovastatin), immunosuppressants (rapamycin, cyclosporin), anti-parasitics
(avermectin), and anti-diabetics (acarbose).
The soil-dwelling actinomycetes and myxobacteria are particularly notable microbial producers of
natural products. We study the biosynthesis and regulation of secondary metabolism in these microorganisms, underpinning our efforts with whole-genome sequencing of model strains. We recently revealed, for example, that the
myxobacterium Sorangium cellulosum
has the largest bacterial genome yet discovered, as well as a capacity to
produce natural products that far exceeds that revealed by standard natural
products chemistry. The data we obtain allow us to optimize metabolite production in the native producers and express
complete pathways in heterologous hosts (such as the Pseudomonads), as well as facilitating attempts to make predictable
alterations to the structures by genetic engineering. Experiments are underway to ‘mine’ the sequenced genomes for novel compounds, using state-of-the-art analytical and
statistical techniques, as well as to deepen our understanding of host
microbiology through functional genomics (transcriptomics and proteomics).We also run a world-wide myxobacterial
strain-discovery program, resulting in the identification of several new
species, genera and families, as well as many potentially novel
metabolites. Selected compounds are
evaluated in mode-of-action studies, using a range of cell lines.
Members of this
interdisciplinary group employ a broad spectrum of techniques, including
microbiology, cell biology, genetics, molecular biology, protein chemistry,
enzymology and analytical chemistry. We
have also established multiple productive collaborations with academic and
industrial partners (see ‘Cooperations’ on side bar).
Molecular and biochemical principles of secondary metabolite formation in myxobacteria and actinomycetes
A large portion of the work in the group addresses the genetics and
mechanistic enzymology of natural product biosynthesis in myxobacteria
and actinomycetes. This work supports attempts to rationally
modify the product structures by genetic engineering.
‘Genome Research on Bacteria Relevant for Agriculture, Environment and
Biotechnology’ – the Sorangium genome project
exploits the data recently made available by the BMB+F-funded genome
sequencing project of the model strain Sorangium cellulosum. The
genome is ‘mined’ for information relevant to optimizing natural
product yields, as well as to generating new, biologically-active
agents, using functional genomics approaches.
Myxobacterial strain discovery
We identify new myxobacterial strains from locations worldwide, using a
set of efficient, in-house purification techniques. The strains
are then analyzed for the production of novel, bioactive compounds
using (bioassay-guided) LC-MS.
Development of improved analytical and statistical methods for mining myxobacterial genomes
We support our genome mining efforts by developing LC-coupled
high-resolution mass spectrometry methodologies, allied with advanced
statistical approaches, such as principle component analysis.
Bioactivity and mode-of-action studies on myxobacterial metabolites and their analogues
Purified natural products and/or their synthetic analogues are evaluated against
a collection of cancer-cell lines. We investigate the
mode-of-action of promising compounds using a range of cell biology
Biotechnological production of bromelain
pineapple protein bromelain is a promising anti-inflammatory
agent. We are collaborating with Ursapharm Arzneimittel GmbH to
develop methods for the recombinant production of bromelain, to enable
its further development as a pharmaceutical agent.