Bioactivity and Metabolome Mining of Deep-Sea Sediment-Derived Microorganisms Reveal New Hybrid PKS-NRPS Macrolactone from PS108-62.

Despite low temperatures, poor nutrient levels and high pressure, microorganisms thrive in deep-sea environments of polar regions. The adaptability to such extreme environments renders deep-sea microorganisms an encouraging source of novel, bioactive secondary metabolites. In this study, we isolated 77 microorganisms collected by a remotely operated vehicle from the seafloor in the Fram Strait, Arctic Ocean (depth of 2454 m). Thirty-two bacteria and six fungal strains that represented the phylogenetic diversity of the isolates were cultured using an One-Strain-Many-Compounds (OSMAC) approach. The crude EtOAc extracts were tested for antimicrobial and anticancer activities. While antibacterial activity against methicillin-resistant (MRSA) and was common for many isolates, only two bacteria displayed anticancer activity, and two fungi inhibited the pathogenic yeast . Due to bioactivity against and rich chemical diversity based on molecular network-based untargeted metabolomics, PS108-62 was selected for an in-depth chemical investigation. A chemical work-up of the SPE-fractions of its dichloromethane subextract led to the isolation of a new PKS-NRPS hybrid macrolactone, versicolide A (), a new quinazoline (-)-isoversicomide A (), as well as three known compounds, burnettramic acid A (), cyclopenol () and cyclopenin (). Their structures were elucidated by a combination of HRMS, NMR, [α], FT-IR spectroscopy and computational approaches. Due to the low amounts obtained, only compounds and could be tested for bioactivity, with inhibiting the growth of (IC 7.2 µg/mL). These findings highlight, on the one hand, the vast potential of the genus to produce novel chemistry, particularly from underexplored ecological niches such as the Arctic deep sea, and on the other, the importance of untargeted metabolomics for selection of marine extracts for downstream chemical investigations.