PUB - Publikationen an der Universität Bielefeld

As the natural producer of acarbose,Actinoplanessp. SE50/110 has high industrial relevance. Like most Actinobacteria, the strain carries several more putative biosynthetic gene clusters (BGCs) to produce further natural products, which are to be discovered. Applying a metabolomics-guided approach, we tentatively identified five further compounds that are produced by the strain: watasemycin, thiazostatin, isopyochelin, pulicatin, and aerugine. A comparison of the genomic context allowed the identification of the putative BGC, which is highly similar to the watasemycin biosynthetic gene cluster ofStreptomyces venezuelae. In addition to the identified molecules, a thiazostatin-like compound was found. Isolation and structure elucidation with 1D and 2D NMR and HRMS were applied. The fraction containingm/z369.0929 [M + H]⁺comprised two highly similar compounds identified as thiazostatin D and thiazostatin E. The compounds possessed the same phenol–thiazole–thiazole molecular scaffold as the previously reported thiazostatin and watasemycin and have anti-proliferative activity against the breast adenocarcinoma cell line MCF7 and human melanoma cell line A2058, while no activity again the non-malignant immortalized fibroblast cell line MRC-5 was observed. We further showed that the manipulation of global transcriptional regulators, withsigH(ACSP50_0507) and anti-anti-σ factor codingACSP50_0284as an example, enabled the production manipulation of the 2-hydroxyphenylthiazoline family molecules. While the manipulation ofsigHenabled the shift in the peak intensities between the five products of this pathway,ACSP50_0284manipulation prevented their production. The production of a highly polar compound withm/z462.1643 [M + H]⁺and calculated elemental composition C₁₉H₂₇NO₁₂was activated under theACSP50_0284expression and is exclusively produced by the engineered strain.