Dihydroanthracenone atropodiastereomers from the endophytic fungus Talaromyces wortmanii with activity against multi-resistant Staphylococcus aureus

Chemical investigation of the endophytic fungal strain Talaromyces wortmannii, isolated from the medicinal plant Aloe vera (Xanthorrhoeaceae), yielded three atropodiastereomeric pairs, including two symmetrical bisdihydroanthracenones, flavomannin A and its new atropisomer flavomannin B, two new asymmetrical bisdihydroanthracenones, and two new dihydroanthracenone/anthraquinone dimers. The planar structures of the new derivatives were unequivocally identified by spectroscopic and mass spectrometric analyses. The axial chirality of the biaryls was deduced from TDDFT ECD and VCD calculations, which however failed to establish the central chirality elements of flavomannin A. All six compounds exhibited antibacterial activity, predominately directed against Staphylococcus aureus, including even high-level (multi)drug-resistant isolates, with MIC values from 4 to 8 µg/mL for the most active compounds. Further Gram-positive genera (Streptococcus, Enterococcus, Bacillus) were moderately affected (MIC 32 to 64 µg/mL). Reporter gene analyses in Bacillus subtilis indicated induction of SOS response for some derivatives, suggesting interference with DNA structure or metabolism. Accordingly, fluorescence microscopy demonstrated defective segregation of the bacterial chromosome and DNA degradation (J. Med. Chem. 2013, 56(8):3257 – 72). The compounds showed no activity when tested against eukaryotic THP-1 cells (leukemia cell line) and BALB cells (mouse embryonic fibroblasts) (> 32 µg/mL).