Sorangium cellulosum

More recently two functionally redundant Sfp-type PPTase, MxPptl and MxPptZ, have been found to differentially activate biosynthetic pathways in Myxococcus xanthus MxPptl and MxPptZ exhibit broad substrate specificity as supported by the fact that the complex PKS-NRPS hydrids epothilone and myxothiazol from Sorangium cellulosum and Stigmatella aurantiaca, respectively, could be expressed in M. xanthus without the need for an external PPTase. 

Ixabepilone (38 Ixempra, BMS-247550 Bristol-Myers Squibb, 2007), a semi-synthetic derivative of epothilone B (39) produced by Sorangium cellulosum, was developed by Bristol-Myers Squibb (BMS) as an anticancer drug (administered through injection) that binds directly to (3-tubulin subunits on microtubules, leading to suppression of microtubule dynamics, blocking of cells in the mitotic phase and ultimately leading to... 

Epothilones A-E (3, 17, 48-50, Fig. 12) were isolated by Hofle and Reichen-bach and co-workers from the myxobacterium Sorangium cellulosum [80, 81]. After initial selection for their antifungal activity, the epothilones were soon shown to possess significant cytotoxicity against mammalian cells, epothilone B being the most active one [82]. Their mode of action was shown to be microtubule stabilization in a fashion very similar to that of... 

Sorangium cellulosum is an ubiquitous soil bacterium that belongs to the order Myxococcales. It has the ability to glide over solid surfaces, to live in a biofilm and form fruiting bodies. Members of this taxon are a particularly rich source of metabolites with remarkable biological activities [177]. From one strain, another example of N-acyl-4-methoxy-3-pyrrolin-2-ones has been isolated. Eliamid (110) has been claimed to have cytostatic, nematocidal and fungicidal activities [178]. 

From strains of Sorangium cellulosum a chlorodivinylether, maracen (110), was isolated. It is active against Mycobacterium tuberculosis (IC99 < 12.5 pg/ml) and only slightly toxic against murine fibroblasts L929 (> 24 pg/ml) [89]. 

Herrmann M, Bohlendorf B, Irschik H, Reichenbach H, Hofle G (1998) Maracin and Maracen New Types of Ethynyl Vinyl Ether and a-Chloro Divinyl Ether Antibiotics from Sorangium cellulosum with Specific Activity Against Mycobacteria. Angew Chem Int Ed 37 1253... 

After the identification of the paclitaxel mechanism of action, several additional microtubule stabilizing agents were discovered from natural sources (Chart 9). Among them, epothilones (12-15) are the most studied and characterized. Epothilones A and B (12,13) were first isolated by Hofle and coworkers [54] from a myxobacterium (Sorangium cellulosum strain 90) in 1993, while their activity in stabilizing microtubule similarly to paclitaxel was reported for the first time by Bollag and co-workers in 1995 [55], Experiments with radio-labeled paclitaxel... 

Patupilone (epothilone B, EPO906) 29 (Novartis) is being evaluated in a Phase III trial for the treatment of patients with ovarian, primary fallopian or peritoneal cancer.191,196,197 Patupilone (then called epothilone B) 29 was first reported by Hofle and co-workers198 200 31 from the myxobacterium Sorangium cellulosum in a 1991 patent application and epothilones were shown by workers at Merck in 1995 to have tubulin-stabilising activity similar to that of paclitaxel 60.31 Ixabepilone 28, which is the semi-synthetic lactam derivative of patupilone 29, was the first epothilone derivative approved (October 2007) for the treatment of breast cancer. 

Gerth K, Bedorf N, Hofle G, Irschik H, Reichenbach H. 97. Epothilons A and B antifungal and cytotoxic compounds from Sorangium cellulosum Myxobacteria. Production, physicochemical and biological properties. J. Antibiot. (Tokyo) 1996 49 560-563. 98. 

Epothilones A (56) and B (57), 16-membered macrocyclic polyketide lactones, were first isolated from the cellulose-degrading myxobac-terium Sorangium cellulosum by Hoefle, Reichenbach, and coworkers (86) as narrow-... 

In a screening of myxobacteria for antibacterial metabolites, the Sorangium cellulosum strain So ce678 was selected for its activity against Staphylococcus aureus [55]. The active compounds were produced as two rather lipophilic active compounds, i.e. tartrolons B (16) and C (17). Tartrolon B was identified as a boric acid ester of tartrolon A3, whereas tartrolon A1 and tartrolon A2 are stereoisomers of tartrolon A3. All components could be chemically converted into eaeh other. 

A partial 16S ribosomal-RNA sequence of CPI 130 matched the genus Streptomyces, most closely the species verticillus. Therefore, this represents the first report of tartrolons from a Streptomyces species, since their only previously reported occurrence was in the myxobacterium Sorangium cellulosum [55, 57, 58]. 

Sorangium cellulosum was fermented in 65 liters at 30 °C with an aeration of 0.15 m air per hour and stirrer speed 150 rpm [4]. The yields of tartrolons A and B are given in Table 10. The main product was tartrolon A whereas in flask culture tartrolon B prevailed. Its proportion was increased on supplying the culture medium with borate. 

A recent example of the power of this technique when applied to natural products is the development of an efficient method for scale-up produchon of epothilone D (Figure 8.6), which entered clinical trials as a potential anticancer agent but has now been disconhnued in favor of a congener, 9,10-didehydroepothilone D. Epothilone D was the most active of the epothilone series isolated from the myxobacte-rium, Sorangium cellulosum, and is the des-epoxy precursor... 

Julien, B., Shah, S., Ziemann, R., Goldman, R., Katz, L., Khosla, C. Isolation and characterization of the epothilone biosynthetic gene cluster from Sorangium cellulosum. Gene 2000, 249, 153-160. 

Rachid, S., Gerth, K., Kochems, I., Muller, R. Deciphering regulatory mechanisms for secondary metabolite production in the myxo-bacterium Sorangium cellulosum So ce56. Mol. Microbiol. 2007, 63, 1783-1796. 

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