Three new quinazoline derivatives (1–3), one new oxepin-containing natural product (4) and four new cyclopenin derivatives (5–7 and 9) have been isolated from an EtOAc extract of the Taiwan Kueishantao hydrothermal vent crab-associated fungus Aspergillus versicolor XZ-4. Their planar structures were established by HRMS, 1D and 2D NMR spectroscopic data analyses. The absolute configurations for compounds 1 and 4 were determined by chiral phase HPLC analysis of their hydrolysis products. The absolute configurations of 2, 3 and 7 were defined mainly by comparison of the quantum chemical TDDFT calculated and the experimental ECD spectra, and the absolute configuration of 5 was deduced from comparison of the optical rotation values reported in the literature. The presence of two atropisomers of 5 was established by NOE analyses. The Ile & Val units in compounds 1–3 allowed the assignment of a new quinazoline skeleton and it's the first time the configuration of isoleucine in the quinazoline skeleton was defined. A series of 7-methoxy cyclopenin derivatives were reported for the first time in this study. The bioevaluation of compounds 5, 7, 8 and 9 revealed inhibitory activities against E. coli at MIC values around 32 μg mL⁻¹.

Standard laboratory cultures have long been known to hinder activation of specific gene clusters which in turn hamper production of secondary metabolites with unique properties due to lack of innovation or the inability to trigger cryptic gene clusters’ expression. Due to challenges related to the avoidance of the isolation of replicated metabolites, resistance-developing pathogens are to be addressed by the scientific community worldwide in order to progress with novel and potent compounds which could further be developed in the future for pharmaceutical usage. This study reports the isolation of novel cryptic antibiotics from a marine fungus Penicillium sp. BB1122 collected from Zhoushan coast by applying the ‘metal-stress’ strategy, here referring to the heavy metal cobalt (6mM). HPLC-guided isolation of four novel and four known compounds belonging to the polyketide class has been carried out where their relative as well as absolute configurations have been determined using spectroscopic analysis techniques as well as by the comparison of theoretically calculated ECD spectrum and the experimental ECD spectrum, respectively. The structures of novel compounds 7 and 8 represent the first example of 2,5-dioxabicyclo[2.2.1]heptane pyrone backbone bearing a migrated polyene chain. The novel compounds 8, 7 and 5 exhibited potent antibiotic properties against S. aureus, B. subtilis and E. coli with MIC values ranging from 0.25 µg/mL to 4 µg/mL. The results showed that cobalt stress is an effective strategy to discover novel antibiotics from microorganisms.