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.Natural products and their derivatives provide the basis for medicines targeting a wide range of human diseases. The Gram-negative myxobacteria, members of the d-subgroup of proteobacteria, are an important source of novel classes of secondary metabolites 1 . Of these, the genus Sorangium is particularly valuable, as 46% of metabolites isolated from myxobacteria 1 , including the potent antitumor compound epothilone 2 , derive from this group. The majority of myxobacterial metabolites are polyketides, nonribosomal polypeptides or hybrids of the two structures, many of which are synthesized on gigantic molecular assembly lines composed of polyketide synthase (PKS) and nonribosomal polypeptide synthetase (NRPS) multienzymes 3 . Sorangium strains exhibit additional characteristic features, including 'social behavior' , cell movement by gliding, biofilm formation and morphological differentiation culminating in complex multicellular structures called fruiting bodies 4 . Three myxobacterial suborders are known 5 and the availability of the genome sequence of Myxococcus xanthus (Cystobacterineae) 6 enables comparative analysis with the Sorangium cellulosum (Sorangiineae) genome to illuminate the basis for several important behavioral and metabolic differences. These include the ability of Sorangium strains to degrade complex plant materials (Fig. 1). S. cellulosum So ce56, an obligate aerobe, was established previously as a model Sorangium strain 7 by virtue of its favorable growth characteristics and ability to differentiate reproducibly under laboratory conditions. It synthesizes the cytotoxic chivosazoles 7 and the catecholate-type siderophores myxochelins 8 . Comparison of the complete genome sequence of strain S. cellulosum

Newcytostatic compounds, tubulysins, were isolated from the culture broth of strains of the myxobacteria Archangium gephyra and Angiococcus disciformis. The compounds are peptides partly consisting of unusual amino acids and are distantly related to the dolastatins. The tubulysins were not active against bacteria and only little against fungi, but showed high cytostatic activity against mammaliancell lines with IC50 values in the picomolar range. An incubation with 50ng/ml tubulysin A led to a complete disappearance of the microtubuli network of the cells within 24 hours. The more active tubulysin D induced multipolar spindles: At 0.5 ng/ml all mitotic cells showed more than four spindle poles.During our screening for new, biologically active metabolites from myxobacteria, we found in the culture broth of different strains of Archangium gephyra activities that were highly cytotoxic for L929 mouse flbroblasts. Bioassay-guided fractionation of culture extracts showed that the activities were due to a group of novel compounds which we called tubulysins. Later, we also found these compoundsin certain strains of the genera Angiococcus, Cystobacter, and Stigmatella. In this paper we describe the production, isolation, and the physico-chemical and biological properties of the tubulysins. Fig. 1 shows the structures of the tubulysins isolated so far, the elucidation of which will be published elsewhere1). The tubulysins are peptides that contain unusual amino acids. The tubulysins A and B have a hydroxyl group on C-31, in contrast to the tubulysins D and E. The tubulysins are distantly related to the dolastatins, which were isolated from the marine slug, Dolabella auricularia2\

In addition to epothilones A (1) and B (2), 37 natural epothilone variants and epothilone-related compounds were isolated from the culture broth of a 700 L fermentation of Sorangium cellulosum, strain So ce90/B2. Of these, only the 12,13-desoxyepothilones, epothilone C (14) and D (15), were produced in significant amounts (3-6 mg/L); the 21-hydroxy derivatives and epothilones E (3) and F (4), in low and variable amounts due to further degradation by the producing organism. Most of the other epothilone variants were produced only in 1-100 microg/L amounts. The new compounds are very similar in structure to the parent compounds 1, 2 and 14, 15 and are presumably the result of the imperfect selectivity of the biosynthetic enzymes for acetate and propionate. Further, epothilones containing an oxazole moiety (10-13) in the side chain instead of a thiazole as well as ring-expanded 18-membered macrolides, epothilones I (30-35), and a ring contracted 14-membered macrolide, epothilone K (36), were found as very minor metabolites. The mutant strain, So ce90/D13, instead of macrolactones, produced short-chain carboxylic acids 40, 41, and 42 bearing the characteristic thiazole side chain. The structures of the new epothilones were elucidated on the basis of comprehensive NMR and MS data. The new epothilone variants were tested in a cytotoxicity assay with mouse fibroblasts (cell line L929), and structure-activity relationships were established. Several new natural epothilones showed activity comparable to 1 and 2, but in no case exceeded that of 2.

, but cannot be converted to PDF. You must view these files (e.g. movies) online.Scheme 1_(structures 1-5)_named.cdx Scheme 2_(structures 6-8)_named.cdx Scheme 3_(structure 9)_named.cdx Scheme 4_(structure 10)_named.cdx Scheme 5_ (structures 11-12) The development of drugs with broad-spectrum antiviral activities is a long pursued goal in drug discovery. It has been shown that blocking co-opted host-factors abrogates the replication of many viruses, yet the development of such host-targeting drugs has been met with skepticism mainly due to toxicity issues and poor translation to in vivo models. With the advent of new and more powerful screening assays and prediction tools, the idea of a drug that can efficiently treat a wide range of viral infections by blocking specific host functions has rebloomed. Here we critically review the state-of-the-art in broad-spectrum antiviral drug discovery. We discuss putative targets and treatment strategies, taking particular focus on natural products as promising starting points for antiviral lead development.

Myxobacteria have it both ways: Whereas the epothilones stabilize the tubulin cytoskeleton and build microtubuli, tubulysins, which have now been isolated from Archangium gephyra and Angiococcus disciformis, have exactly the opposite effect. They induce the disintegration of the microtubuli, and even picomolar concentrations can cause cell death by apoptosis. Their effect on cell cultures exceeds that of the most active epothilones by 50‐fold.