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

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.

Miniaturized Cultivation Profiling Returns Indolo-Sesquiterpene Michael Adducts from the Australian Soil-Derived Aspergillus terreus CMB-SWF012.

An integrated program of chemical profiling (GNPS) coupled with an expanded format 24-well-plate miniaturized cultivation profiling (MATRIX) utilizing traditional as well as grain/pulse and cereal media permitted rapid prioritization of Aspergillus terreus CMB-SWF012 as a source of unprecedented natural products. Scaled-up cultivation on rice and PDA yielded the rare tripeptides asterripeptides A-C (1-3), new indolo-sesquiterpene Michael adducts terreusides A and B (4 and 5), and known precursors asterresin A (6) and (+)-giluterrin (7). Structures for 1-7 were assigned by detailed spectroscopic and chemical analysis and biosynthetic considerations.

Noonindoles G-L: Indole Diterpene Glycosides from the Australian Marine-Derived Fungus Aspergillus noonimiae CMB-M0339.

Fungal indole diterpenes (IDTs) occupy a valuable region of bioactive natural product chemical space, displaying potent and selective inhibition of therapeutically important ion channels and with potential application in the treatment of glaucoma, cancer, and neurodegenerative diseases, as well as insecticides and antivirals. We have employed an integrated workflow of analytical scale chemical profiling using GNPS (Global Natural Products Social molecular networking) and cultivation profiling (also known as "MATRIX" miniaturized microbioreactor) to detect, prioritize, optimize the production, isolate, characterize, and identify a new series of indole diterpenes, noonindoles G-L (7-12), from an Australian marine-derived fungus, Aspergillus noonimiae CMB-M0339. The first reported examples of IDT glycosides, the molecular structures for 7-12, were assigned on the basis of detailed spectroscopic analysis and biosynthetic considerations.