A genomic screening approach to the structure-guided identification of drug candidates from natural sources.

The potential of actinomycetes to produce natural products has been exploited for decades. Recent genomic sequence analyses have revealed a previously unrecognized biosynthetic potential and diversity. In order to rationally exploit this potential, we have developed a sequence-guided genetic screening strategy. In this "genome mining" approach, genes that encode tailoring enzymes from natural product biosyntheses pathways serve as indicator genes for the identification of strains that have the genetic potential to produce natural products of interest. We chose halogenases, which are known to be involved in the synthesis of halometabolites as representative examples. From PCR screening of 550 randomly selected actinomycetes strains, we identified 103 novel putative halogenase genes. A phylogenetic analysis of the corresponding putative halogenases, and the determination of their sequential context with mass spectrometric analysis of cultures filtrates revealed a distinct correlation between the sequence and secondary metabolite class of the halometabolite. The described screening strategy allows rapid access to novel natural products with predetermined structural properties.

Ripromycin and other polycyclic macrolactams from Streptomyces sp. Tü 6239: taxonomy, fermentation, isolation and biological properties.

Strain Tü 6239 was isolated from a soil sample collected in Brazil and determined as a new species of the genus Streptomyces. In the course of our HPLC-diode array screening program three metabolites were detected in the culture filtrate and mycelium extracts of strain Tü 6239. They were characterised as members of the macrolactam group, the new compound ripromycin (1), the previously described ikarugamycin (2) and a new derivative of it, ikarugamycin epoxide (3). They show antibiotic activities against gram-positive bacteria and cytostatic effects to various human tumor cell lines.

Screening for biologically active metabolites with endosymbiotic bacilli isolated from arthropods.

Endosymbiotic bacteria from the genus Bacillus were isolated from different compartments of the gut of various members of insects (Hexapoda) and millipedes (Diplopoda). They were grown in submerged culture and investigated by biological assays and HPLC-diode array analysis regarding their production of bioactive metabolites, which were isolated and determined in structure. Known compounds and yet unknown derivatives from the primary metabolism were detected, as well as antibacterially and antifungally acting peptide antibiotics.

Simocyclinones, novel cytostatic angucyclinone antibiotics produced by Streptomyces antibioticus Tü 6040 II. Structure elucidation and biosynthesis.

The simocyclinones D4 (1) and D8 (2), members of a novel class of antibiotics, were isolated from the mycelial extract of Streptomyces antibioticus Tü 6040 and consist of angucyclinone, deoxysugar, octatetraene dicarboxylate and aminocoumarin structural elements. The structure elucidation was done by one and two dimensional NMR experiments, and other spectroscopic methods in combination with incorporation experiments using 13C labelled precursors.