The genus Sorangium synthesizes approximately half of the secondary metabolites isolated from myxobacteria, including the anti-cancer metabolite epothilone. We report the complete genome sequence of ...the model Sorangium strain S. cellulosum So ce56, which produces several natural products and has morphological and physiological properties typical of the genus. The circular genome, comprising 13,033,779 base pairs, is the largest bacterial genome sequenced to date. No global synteny with the genome of Myxococcus xanthus is apparent, revealing an unanticipated level of divergence between these myxobacteria. A large percentage of the genome is devoted to regulation, particularly post-translational phosphorylation, which probably supports the strain's complex, social lifestyle. This regulatory network includes the highest number of eukaryotic protein kinase-like kinases discovered in any organism. Seventeen secondary metabolite loci are encoded in the genome, as well as many enzymes with potential utility in industry.
Reinvestigation of the production of the unusual polyene carboxylic acid serpentene (1a) from Streptomyces sp. Tü 3851 revealed the presence of additional polyene carboxylic acids. The methyl esters ...of the new all-trans serpentene (2) and four new dicarboxylic acids (3−6) were isolated after methylation of the isolated polyene fraction. The dicarboxylic acids might result from ω- and β-oxidation of the parent compounds 1 and 2.
Polyunsaturated fatty acids (PUFAs), particularly the omega-3 long-chain PUFAs (LC-PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are well known for their beneficial health ...effects. The obvious limitation of the present EPA/DHA key source, fish oil, demands for alternative and sustainable PUFA resources and several biotechnological approaches addressing this problem are currently under development. Different marine microorganisms are known to produce PUFAs
de novo
under strictly anaerobic conditions employing polyketide synthase (PKS)-like enzymes known as PUFA synthases. Here, we report for the first time the characterization of such PUFA synthases from terrestrial origin. Two distinct types of PUFA biosynthetic gene clusters were discovered, originating from linoleic acid producing myxobacteria of the genus
Sorangium
as well as from species of the recently discovered myxobacterial genus
Aetherobacter
, that turned out to be prolific producers of EPA and DHA. The identified biosynthetic pathways differ significantly from the marine systems in terms of gene organization, catalytic domain arrangement, and sequence identity of the encoded PUFA synthases. Notably, a unique domain, which most likely acts as 1-acylglycerol-3-phosphate
O
-acyltransferase, was identified in these myxobacterial PUFA synthases. As the native producer strains grow slowly, are difficult to handle, and genetic modification has proven difficult, synthetic biotechnology approaches were applied to establish a heterologous production platform in the myxobacterial model strain
Myxococcus xanthus
.
The first terrestrial polyketide synthase-like pathways for the biosynthesis of polyunsaturated fatty acids have been identified and characterized.
Myxobacteria produce an immense variety of natural products with useful biological activities. This review highlights recent advances to evaluate and further explore their biosynthetic potential for ...drug discovery, with particular focus on polyketide synthase and non-ribosomal peptide synthetase-derived secondary metabolites.
Natural products of microbial origin are widely used as pharmaceuticals and in agrochemistry. These compounds are often biosynthesized by multifunctional megasynthetases whose genetic engineering and ...heterologous expression offer considerable promise, especially if the natural hosts are genetically difficult to handle, slow growing, unculturable, or even unknown. We describe a straightforward strategy that combines the power of advanced DNA engineering (recombiogenic cloning) in
Escherichia coli with the utility of pseudomonads as the heterologous host for the analysis and mutagenesis of known and unknown secondary metabolite pathways. The myxochromide S biosynthetic gene cluster from
Stigmatella aurantiaca was rebuilt and engineered in
E. coli to contain the elements required for expression in pseudomonads. The successful production in
Pseudomonas putida, at unprecedented levels, demonstrates the feasibility of the new approach to the analysis and mutagenesis of these important pathways.
Bengamide, aus marinen Schwämmen stammende und als Inhibitoren der Methionin‐Aminopeptidase (MetAP) charakterisierte Naturstoffe, wurden intensiv als Wirkstoffe gegen Krebs erforscht. In einem ...multidisziplinären Forschungsprojekt haben wir die Bereitstellung von Bengamiden über Fermentation des terrestrischen Myxobakteriums M. virescens, die Aufklärung ihrer Biosynthese und die Optimierung ihrer Eigenschaften als Arzneistoff‐Leitstrukturen untersucht. Die Charakterisierung des Biosyntheseweges zeigte auf, dass bakterielle Resistenz gegenüber Bengamiden durch Leu154 des myxobakteriellen MetAP‐Proteins vermittelt wird, und ermöglichte den Transfer des gesamten Biosynthesegenclusters in den geeigneteren Produktionsstamm M. xanthus DK1622. Eine Kombination aus Semisynthese mikrobiell gewonnener Bengamide und Totalsynthese führte zum optimierten Derivat 8 a. Die nanomolare zelluläre Wirksamkeit und die hohe metabolische Stabilität waren mit einer verbesserten Halbwertszeit in Mäusen sowie mit Antitumor‐Effizienz in einem Melanom‐Mausmodell verbunden.
Ein terrestrischer Tauchgang zu Bengamiden: Bengamide, aus marinen Schwämmen stammende Naturstoffe, wurden in einem terrestrischen Produzenten hergestellt. Ihre Biosynthese und Selbstresistenzmechanismen gegen Methionin‐Aminopeptidasen wurden aufgeklärt, eine heterologe Expressionsplattform wurde etabliert und auf ihre pharmakologischen Eigenschaften optimiert.
The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a ...worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification.
The structurally unique leupyrrins A1 (1), A2 (2), B1 (3), B2 (4), C (5), and D (6) were isolated as one of three groups of secondary metabolites from Sorangium cellulosum strains So ce705 and So ...ce690. An unusually substituted γ-butyrolactone ring and pyrrole and oxazoline rings are embedded in a nonsymmetric macrodiolide core structure, giving rise to compounds 1−6 as members of a novel class of secondary metabolites. Leupyrrin A1 (1) shows good biological activity against various fungi and eukaryotic cells.
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