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Pyrrolopyrimidines are an important class of natural products with a broad spectrum of biological activities, including antibacterial, antifungal, antiviral, anticancer or anti-inflammatory. Here, we present the identification of a biosynthetic gene cluster from the rare actinomycete strain Kutzneria albida DSM 43870, which leads to the production of huimycin, a new member of the pyrrolopyrimidine family of compounds. The huimycin gene cluster was successfully expressed in the heterologous host strain Streptomyces albus Del14. The compound was purified, and its structure was elucidated by means of nuclear magnetic resonance spectroscopy. The minimal huimycin gene cluster was identified through sequence analysis and a series of gene deletion experiments. A model for huimycin biosynthesis is also proposed in this paper.

Natural products produced by bacteria found in unusual and poorly studied ecosystems, such as Lake Baikal, represent a promising source of new valuable drug leads. Here we report the isolation of a new Streptomyces sp. strain IB201691-2A from the Lake Baikal endemic mollusk Benedictia baicalensis. In the course of an activity guided screening three new angucyclines, named baikalomycins A-C, were isolated and characterized, highlighting the potential of poorly investigated ecological niches. Besides that, the strain was found to accumulate large quantities of rabelomycin and 5-hydroxy-rabelomycin, known shunt products in angucyclines biosynthesis. Baikalomycins A-C demonstrated varying degrees of anticancer activity. Rabelomycin and 5-hydroxy-rabelomycin further demonstrated antiproliferative activities. The structure elucidation showed that baikalomycin A is a modified aquayamycin with β-d-amicetose and two additional hydroxyl groups at unusual positions (6a and 12a) of aglycone. Baikalomycins B and C have alternating second sugars attached, α-l-amicetose and α-l-aculose, respectively. The gene cluster for baikalomycins biosynthesis was identified by genome mining, cloned using a transformation-associated recombination technique and successfully expressed in S. albus J1074. It contains a typical set of genes responsible for an angucycline core assembly, all necessary genes for the deoxy sugars biosynthesis, and three genes coding for the glycosyltransferase enzymes. Heterologous expression and deletion experiments allowed to assign the function of glycosyltransferases involved in the decoration of baikalomycins aglycone.

Microbial secondary metabolites are known to be an excellent source for novel therapeutic agents. Among other microorganisms, myxobacteria are continuously providing new biologically active natural compounds with unique structures. Here, chemical screening of these gram-negative bacteria has resulted in the identification of two new structural classes of natural products along with a new derivative of a sponge-derived natural product. In this thesis, isolation, structural elucidation, and biological activity of these new secondary metabolites are presented. New catecholate-type siderophores, hyalachelins A-C, were isolated from the strain belonging to the underexplored species Hyalangium minutum. Their complete 3D structure was obtained by combining the spectroscopic data and quantum mechanical calculations. Iron binding activity of hyalachelins was determined by CAS assay. Moreover, novel polyketides, named cystochromones, were isolated from Cystobacter sp. Cystochromones bear a chromone ring that is substituted by a long aliphatic chain on position C-5 which is not preceded among natural chromones. Additionally, a biosynthetic pathway was proposed on the basis of the results of the feeding experiments. Furthermore, a new derivative of the marine sponge-derived peptide microsclerodermin was isolated from the terrestrial myxobacterium. This result represents the rare example of isolation of same compounds from terrestrial and marine sources. Mikrobielle Naturstoffe sind bekanntermaßen eine ergiebige Quelle für neue therapeutische Wirkstoffe. Aus Myxobakterien werden fortwährend neue biologisch aktive Naturstoffe mit einzigartigen Strukturen isoliert. Ein chemisches screening dieser Gram-negativen Bakterien resultierte in der Identifizierung von zwei strukturell neuen Klassen von Sekundärmetaboliten und einem neuen Derivat eines bereits bekannten Naturstoffes. In der vorliegenden Arbeit werden die Isolierung, Strukturaufklärung und die biologischen Aktivitäten dieser Substanzen diskutiert. Die Hyacheline A-C, neue Siderophore vom Catecholat-Typ, wurden aus einem Stamm der wenig erforschten myxobakteriellen Spezies Hyalangium minutum isoliert. Die dreidimensionale Struktur der Hyacheline wurde mittels Kombination von spektroskopischen Daten mit quantenmechanischen Berechnungen aufgeklärt, sowie ihr Eisen-Bindungsverhalten anhand von CAS Assays bestimmt. Die Cystochromone wurden aus Extrakten von Cystobacter sp. isoliert. Die chromonartigen Polyketide tragen an Position C-5 des Chromonsystems einen langkettigen aliphatischen Rest. Diese Substitution ist von natürlichen Chromonen bisher nicht bekannt. Auf Basis von Fütterungsexperimenten konnte ein Biosyntheseweg für die Cystochromone vorgeschlagen werden. Weiterhin wurde ein neues Derivat der Mikrosklerodermine aus dem Extrakt eines terrestrischen Myxobakteriums isoliert. Diese Naturstoffe waren bisher aus Meeresschwämmen bekannt und stellen ein Beispiel des selten beschriebenen Falles eines gemeinsamen oder ähnlichen Sekundärmetabolismus von marinen und terrestrischen Mikroorganismen dar.