Jugiones A–D: Antibacterial Xanthone–Anthraquinone Heterodimers from Australian Soil-Derived Penicillium shearii CMB-STF067

Abstract

The Australian roadside soil-derived fungus Penicillium shearii CMB-STF067 was prioritized for chemical investigation based on an SDA cultivation extract exhibiting both antibacterial properties and natural products with unprecedented molecular formulae (GNPS). Subsequent miniaturized 24-well plate cultivation profiling (MATRIX) identified red rice as optimal for the production of the target chemistry, with scaled-up cultivation, extraction and fractionation yielding four new xanthone–anthraquinone heterodimers, jugiones A–D (1–4), whose structures were assigned by detailed spectroscopic analysis and biosynthetic considerations. Of note, where 1–2 and 4 were active against the Gram-positive bacteria vancomycin-resistant Enterococcus faecalis (IC50 2.6–3.9 μM) and multiple-drug-resistant clinical isolates of Staphylococcus aureus (IC50 1.8–6.4 μM), and inactive against the Gram-negative bacteria Escherichia coli (IC50 > 30 μM), the closely related analog 3 exhibited no antibacterial properties (IC50 > 30 μM). Furthermore, where 1 was cytotoxic to human carcinoma (IC50 9.0–9.8 μM) and fungal (IC50 4.1 μM) cells, 2 and 4 displayed no such cytotoxicity (IC50 > 30 μM), revealing an informative structure activity relationship (SAR). We also extended the SAR study to other known compounds of this heterodimer class, which showed that the modification of ring G can reduce or eliminate the cytotoxicity while retaining the antibacterial activity.