Metabolomics-Driven Discovery of Meroterpenoids from a Mussel- Derived Penicillium ubiquetum Thi Phuong Thuy Hoang, †,‡ Catherine Roullier,* ,†,§ Marie-Claude Boumard, † Thibaut Robiou du Pont, † Hassan Nazih, † Jean-Franç ois Gallard, ⊥ Yves Franç ois Pouchus, † Mehdi A. Beniddir, ∥ and Olivier Grovel †,§ † EA 2160 - Mer Molé cules Santé , Université de Nantes, 44035 Nantes Cedex 1, France ‡ Phu Tho College of Pharmacy, 290000 Phu Tho, Vietnam § Corsaire-ThalassOMICS Metabolomics Facility, Biogenouest, Université de Nantes, Nantes, France ⊥ Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris Saclay, 91198 Gif-sur-Yvette, France ∥ E ́ quipe “Pharmacognosie-Chimie des Substances Naturelles” BioCIS, Univ. Paris-Sud, CNRS, Université Paris Saclay, 92290 Châ tenay-Malabry, France * S Supporting Information ABSTRACT: Penicillium ubiquetum MMS330 isolated from the blue mussel Mytilus edulis collected on the Loire estuary in France was here investigated. As very few secondary metabolites have been documented for this species, its metabolome was studied following the OSMAC approach to enhance as many biosynthetic pathways as possible. Interestingly, HPLC-HRMS based hierarchical clustering analysis together with MS/MS molecular networking high- lighted the selective overproduction of some structurally related compounds when the culture was performed on seawater CYA (Czapek Yeast extract Agar) medium. Mass- guided purification from large scale cultivation on this medium led to the isolation of nine meroterpenoids including two new analogues, 22-deoxyminiolutelide A (1) and 4-hydroxy-22-deoxyminiolutelide B (2), together with seven known compounds (3−9). The structures of 1 and 2 were elucidated on the basis of HR-ESIMS and NMR spectroscopic data analysis. Furthermore, NMR signals of 22-deoxyminiolutelide B (3) were reassigned. I n recent years, marine fungi have attracted much attention, as demonstrated by the considerable increase in articles documenting their biodiversity, chemodiversity, and potential biotechnological applications. 1 The discovery of new natural products from fungi isolated in marine habitats has increased rapidly in the past few years. 2−5 Marine-derived fungi are now considered as a promising resource to provide novel structures with new modes of action that can cover biologically relevant chemical space. 6,7 Moreover, marine fungi have also been hypothesized to be potentially responsible for atypical toxicities of shellfishes such as bivalve molluscs, implying contamination with toxic compounds of fungal origin. 8 Investigation of their metabolism is then relevant for different research areas, from natural product chemistry and drug discovery to aquaculture 9 and food consumption safety. Following our ongoing work on the study of fungal metabolites of marine origin, a strain of Penicillium ubiquetum Houbraken, Frisvad, and Samson isolated from the blue mussel Mytilus edulis 8 was here investigated, as Penicillium strains isolated from bivalve molluscs have been shown to produce extracts exhibiting a higher cytotoxicity than extracts from Penicillium strains isolated from the surrounding marine environment. 10 The species Penicillium ubiquetum was first described in 2011, 11 and very little is known about its specialized metabolites. Only a few compounds including citrinin, terrein, and okaramin derivatives were briefly reported as taxonomic markers of this species. 11 An extensive investigation of the metabolome of this species was then needed, in order to reveal new compounds and/or highlight toxic metabolites that could be produced in the mussel. As reported in many studies, specialized metabolite production varies in microorganisms according to culture conditions. 12−15 Expression of biosynthetic gene clusters implied in the production of secondary metabolites can effectively be modified depending on the media. 16,17 To induce the expression of as many biosynthetic pathways as possible in a strain, one strategy consists of culturing the fungus on di fferent media and exploring the overall metabolome. Interestingly, media with increased salinity create Received: July 12, 2018 Article pubs.acs.org/jnp Cite This: J. Nat. Prod. XXXX, XXX, XXX-XXX © XXXX American Chemical Society and American Society of Pharmacognosy A DOI: 10.1021/acs.jnatprod.8b00569 J. Nat. Prod. XXXX, XXX, XXX−XXX Downloaded via KAOHSIUNG MEDICAL UNIV on November 8, 2018 at 23:14:47 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.