Mesoporous Silica as an Alternative Vehicle to Overcome Solubility Limitations.

Toxicological studies are a part of the drug development process and the preclinical stages, for which suitable vehicles ensuring easy and safe administration are crucial. However, poor aqueous solubility of drugs complicates vehicle screening for oral administration since non-aqueous solvents are often not tolerable. In the case of the anti-infective corallopyronin A, currently undergoing preclinical investigation for filarial nematode and bacterial infections, commonly used vehicles such as polyethylene glycol 200, aqueous solutions combined with cosolvents or solubilizers, or aqueous suspension have failed due to insufficient tolerability, solubility, or the generation of a non-homogeneous suspension. To this end, the aim of the study was to establish an alternative approach which offers suitable tolerability, dissolution, and ease of handling. Thus, a corallopyronin A-mesoporous silica formulation was successfully processed and tested in a seven-day toxicology study focused on Beagle dogs, including a toxicokinetic investigation on day one. Sufficient tolerability was confirmed by the vehicle control group. The vehicle enabled high-dose levels resulting in a low-, middle-, and high-dose of 150, 450, and 750 mg/kg. Overall, it was possible to achieve high plasma concentrations and exposures, leading to a valuable outcome of the toxicology study and establishing mesoporous silica as a valuable contender for challenging drug candidates.

Discovery and characterisation of a broderol-like illudin, omphaderol in the mycelial extracts of Omphalotus mexicanus (Omphalotaceae) using UPLC-QTOF-MS and NMR spectroscopy.

INTRODUCTION: The genus Omphalotus, in particular the "Jack-O'Lantern mushrooms" Omphalotus illudens and Omphalotus olearius, are famous for the production of the DNA-alkylating illudins. A lesser-known species, Omphalotus mexicanus, native to Central America, also produces cytotoxic illudins S and M, but its minor secondary metabolites are yet to be investigated. OBJECTIVE: To identify, isolate, and elucidate the structure of novel secondary metabolites of the illudin family in mycelial extracts of O. mexicanus from submerse cultivation. METHODOLOGY: A fermentation of the fungus in 15 L stirred tank bioreactors is described. Mycelial extracts were separated using a combination of flash chromatography with preparative RP-C18 high-performance liquid chromatography (HPLC). Analysis of metabolites was done using an ultrahigh-performance liquid chromatography ultraviolet diode array detector (UPLC-UV-DAD) system coupled to an electrospray ionisation quadrupole time-of-flight (ESI-QTOF) mass spectrometer. Structures were elucidated using one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance spectroscopy (NMR) techniques followed by comparison of experimental and simulated electronic circular dichroism (ECD) spectra to determine absolute configurations. RESULTS: Two novel illudin derivatives, for which we propose the names omphaderol (1) and illudaneol B (2), as well as illudaneol (3) and the unusual cyclobutylcyclopentane illudosin (4), were isolated from the mycelia and characterised. CONCLUSION: Particularly the illudaneol derivatives with their high titers may be potential building blocks for an alternative semisynthetic route to new illudin derivatives with improved medical properties. Additionally, the findings improve the knowledge of minor illudin compounds in the mycelial extract of this fungus and may be of significance for future biosynthetic studies of the illudins.

Analogs of the carotane antibiotic fulvoferruginin from submerged cultures of a Thai Marasmius sp.

A recent find of a Marasmius species in Northern Thailand led to the isolation of five unprecedented derivatives of the carotane antibiotic fulvoferruginin (1), fulvoferruginins B-F (2-6). The structures of these sesquiterpenoids were elucidated using HRESIMS, 1D and 2D NMR, as well as CD spectroscopy. Assessing the bioactivity, fulvoferruginin emerged as a potent cytotoxic agent of potential pharmaceutical interest.

Author Correction: The planctomycete Stieleria maiorica Mal15T employs stieleriacines to alter the species composition in marine biofilms.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: The planctomycete Stieleria maiorica Mal15T employs stieleriacines to alter the species composition in marine biofilms.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Stieleriacines, N-Acyl Dehydrotyrosines From the Marine Planctomycete Stieleria neptunia sp. nov.

Bacteria of the phylum Planctomycetes occur ubiquitously in marine environments and play important roles in the marine nitrogen- and carbon cycle, for example as scavengers after phototrophic blooms. Here, we describe the isolation and characterization of the planctomycetal strain Enr13T isolated from a Posidonia sp. biofilm obtained from seawater sediment close to Panarea Island, Italy. Phylogenetic tree reconstruction based on 16S rRNA gene sequences and multi-locus sequence analysis supports the delineation of strain Enr13T from characterized species part of the phylum of Planctomycetes. HPLC-MS analysis of culture broth obtained from strain Enr13T revealed the presence of lipophilic metabolites, of which the major compound was isolated by preparative reversed-phase HPLC. The structure of this compound, named stieleriacine D (1), was elucidated utilizing HRESIMS, 1D- and 2D-NMR data as a new N-acylated dehydrotyrosine derivative. Its biosynthesis was proposed based on an in silico gene cluster analysis. Through analysis of the MS/MS spectrum of 1 and its minor derivative, stieleriacine E (2), it was possible to assign the structure of 2 without isolation. 1 showed antibacterial activity, however, the wide distribution of structurally related compounds indicates a potential role as a signaling molecule.

The planctomycete Stieleria maiorica Mal15T employs stieleriacines to alter the species composition in marine biofilms.

Bacterial strains of the phylum Planctomycetes occur ubiquitously, but are often found on surfaces of aquatic phototrophs, e.g. alga. Despite slower growth, planctomycetes are not outcompeted by faster-growing bacteria in biofilms on such surfaces; however, strategies allowing them to compensate for slower growth have not yet been investigated. Here, we identified stieleriacines, a class of N-acylated tyrosines produced by the novel planctomycete Stieleria maiorica Mal15T, and analysed their effects on growth of the producing strain and bacterial species likely co-occurring with strain Mal15T. Stieleriacines reduced the lag phase of Mal15T and either stimulated or inhibited biofilm formation of two bacterial competitors, indicating that Mal15T employs stieleriacines to specifically alter microbial biofilm composition. The genetic organisation of the putative stieleriacine biosynthetic cluster in strain Mal15T points towards a functional link of stieleriacine biosynthesis to exopolysaccharide-associated protein sorting and biofilm formation.

Antifungal Sesquiterpenoids, Rhodocoranes, from Submerged Cultures of the Wrinkled Peach Mushroom, Rhodotus palmatus.

Seven previously unknown sesquiterpenoids and norsesquiterpenoids, rhodocoranes F-L (1-7), were isolated from the fermentation broth of the basidiomycete Rhodotus palmatus. Their structures were elucidated utilizing 1D and 2D NMR techniques as well as HRESIMS; they are unusual noracorane, spiro[4.4]nonene, and acorane-type sesquiterpenoids. They include the first naturally occurring cyclopentylidenefuranones (3-5) and the new tricyclic scaffold of 7. Metabolites 1-7 exhibited a general mild antimycotic activity, while 1-3 also displayed cytotoxic effects.

Antiviral Meroterpenoid Rhodatin and Sesquiterpenoids Rhodocoranes A-E from the Wrinkled Peach Mushroom, Rhodotus palmatus.

Rhodatin (1), a meroterpenoid featuring a unique pentacyclic scaffold with both spiro and spiroketal centers, and five unusual acorane-type sesquiterpenoids, named rhodocoranes A-E (2-6, respectively), are the first natural products isolated from the basidiomycete Rhodotus palmatus. Their structures were elucidated by two-dimensional NMR experiments and HRESIMS, while the absolute configuration of the substance family was determined by Mosher's method utilizing 2. Rhodatin strongly inhibited hepatitis C virus, whereas 4 displayed cytotoxicity and selective antifungal activity.

Biological and chemical diversity go hand in hand: Basidiomycota as source of new pharmaceuticals and agrochemicals.

The Basidiomycota constitutes the second largest higher taxonomic group of the Fungi after the Ascomycota and comprises over 30.000 species. Mycelial cultures of Basidiomycota have already been studied since the 1950s for production of antibiotics and other beneficial secondary metabolites. Despite the fact that unique and selective compounds like pleuromutilin were obtained early on, it took several decades more until they were subjected to a systematic screening for antimicrobial and anticancer activities. These efforts led to the discovery of the strobilurins and several hundreds of further compounds that mainly constitute terpenoids. In parallel the traditional medicinal mushrooms of Asia were also studied intensively for metabolite production, aimed at finding new therapeutic agents for treatment of various diseases including metabolic disorders and the central nervous system. While the evaluation of this organism group has in general been more tedious as compared to the Ascomycota, the chances to discover new metabolites and to develop them further to candidates for drugs, agrochemicals and other products for the Life Science industry have substantially increased over the past decade. This is owing to the revolutionary developments in -OMICS techniques, bioinformatics, analytical chemistry and biotechnological process technology, which are steadily being developed further. On the other hand, the new developments in polythetic fungal taxonomy now also allow a more concise selection of previously untapped organisms. The current review is dedicated to summarize the state of the art and to give an outlook to further developments.

Antiviral 4-Hydroxypleurogrisein and Antimicrobial Pleurotin Derivatives from Cultures of the Nematophagous Basidiomycete Hohenbuehelia grisea.

4-Hydroxypleurogrisein, a congener of the anticancer-lead compound pleurotin, as well as six further derivatives were isolated from the basidiomycete Hohenbuehelia grisea, strain MFLUCC 12-0451. The structures were elucidated utilizing high resolution electron spray ionization mass spectrometry (HRESIMS) and 1D and 2D nuclear magnetic resonance (NMR) spectral data and evaluated for their biological activities; for leucopleurotin, we provide Xray data. While most congeners showed moderate antimicrobial and cytotoxic activity, 4-hydroxypleurogrisein emerged as an inhibitor of hepatitis C virus infectivity in mammalian liver cells.

Cysteine-Derived Pleurotin Congeners from the Nematode-Trapping Basidiomycete Hohenbuehelia grisea.

The discovery of a Hohenbuehelia grisea specimen during a field trip in Northern Thailand led to the isolation and identification of three novel sulfur-bearing derivatives of dihydropleurotinic acid (4). Thiopleurotinic acid A (1) was established by the interpretation of spectral data (HRESIMS, 2D-NMR) as a 2-hydroxy-3-mercaptopropanoic acid conjugate of dihydropleurotinic acid. Thiopleurotinic acid B (2) was shown to be the N-acetylcysteine conjugate of 4. A third compound (3) was established as a thiazole-containing derivative. Through feeding experiments with [U-13C3, 15N]-l-cysteine the formation of all three metabolites was shown to involve cysteine condensation with 4. The decreased cytotoxicity and antimicrobial activities of the new derivatives 1-3, compared to the parent compound 4, indicate a possible detoxification pathway of filamentous fungi.