Metabolomics-Guided Discovery, Isolation, Structure Elucidation, and Bioactivity of Myropeptins C–E from Myrothecium inundatum

Abstract

The saprotrophic filamentous fungus Myrothecium inundatum represents a chemically underexplored ascomycete with a high number of putative biosynthetic gene clusters in its genome. Here, we present new linear lipopeptides from nongenetic gene activation experiments using nutrient and salt variations. Metabolomics studies revealed four myropeptins, and structural analyses by NMR, HRMS, Marfey’s analysis, and ECD assessment for their helical properties established their absolute configuration. A myropeptin biosynthetic gene cluster in the genome was identified. The myropeptins exhibit general nonspecific toxicity against all cancer cell lines in the NCI-60 panel, larval zebrafish with EC50 concentrations of 5–30 μM, and pathogenic bacteria and fungi (MICs of 4–32 μg/mL against multidrug-resistant S. aureus and C. auris). In vitro hemolysis, cell viability, and ionophore assays indicate that the myropeptins target mitochondrial and cellular membranes, inducing cell depolarization and cell death. The toxic activity is modulated by the length of the lipid side chain, which provides valuable insight into their structure–activity relationships.

Ormosianines A–P, Structurally Diverse Quinolizidine Alkaloids with AChE Inhibitory Effects from Ormosia yunnanensis

“…Semipreparative HPLC was performed on a Waters 600 binary pump system with a Waters 2489 detector (210 and 230 nm) using a YMC-Pack ODS-A column (250 × 10 mm, S-5 μm, 12 nm, Tokyo, Japan) or an X-Bridge Prep-C 18 HPLC column (10 × 250 mm, 5 μm, Waters, Ireland). The other experimental procedures were carried out as previously described. , …”

“…The other experimental procedures were carried out as previously described. 39,40 Plant Material. Stems and leaves of O. yunnanensis were collected in Xishuangbanna Dai Autonomous Prefecture, south of Yunnan Province, China.…”

Current Perspectives of Antifungal Therapy: A Special Focus on <em>Candida auris</em>

“…A group of new linear lipopeptides (Myropeptin C−E and Myropeptin A1) isolated from saprotrophic filamentous fungus Myrothecium inundatum, also produced good inhibition in C. auris cells. In vitro hemolysis, cell viability, and ionophore assays indicated that these compounds target mitochondrial and cellular membranes, inducing cell depolarization and cell death [65]. Subsequentely, Hakuhybotrol along with six known cladobotric acids F, E, H, A, pyrenulic acid A and F2928-1 were isolated from culture broth of Hypomyces pseudocorticiicola FKA-73.…”

Current Perspectives of Antifungal Therapy: A Special Focus on Candida auris

“…A group of new linear lipopeptides (Myropeptin C–E and Myropeptin A1), isolated from the saprotrophic filamentous fungus Myrothecium inundatum , showed good inhibition of C. auris cells. In vitro hemolysis, cell viability, and ionophore assays indicated that these compounds target mitochondrial and cellular membranes, inducing cell depolarization and cell death [ 66 ]. Subsequently, hakuhybotrol along with six known cladobotric acids F, E, H, A, pyrenulic acid A, and F2928-1 were isolated from a culture broth of Hypomyces pseudocorticiicola FKA-73.…”