Dermacozines H–J Isolated from a Deep-Sea Strain of <i>Dermacoccus abyssi</i> from Mariana Trench Sediments

<i>Dermacoccus abyssi</i> sp. nov. strains MT1.1 and MT1.2 are actinomycetes isolated from a Mariana Trench sediment at a depth of 10 898 m. The fermentation process using complex media led to the production of three new pigmented heteroaromatic (oxidized and reduced) phenazine compounds, dermacozines H–J (<b>1</b>–<b>3</b>). Extensive use was made of 1D and 2D NMR experiments and high-resolution MS to determine the structures of the compounds. The new dermacozines showed radical scavenging activity, and the highest activity was observed for dermacozine H (<b>1</b>), with an IC₅₀ value of 18.8 μM

Zebrafish-Based Discovery of Antiseizure Compounds from the Red Sea: Pseurotin A₂ and Azaspirofuran A

In search for novel antiseizure drugs (ASDs), the European FP7-funded PharmaSea project used zebrafish embryos and larvae as a drug discovery platform to screen marine natural products to identify promising antiseizure hits in vivo for further development. Within the framework of this project, seven known heterospirocyclic γ-lactams, namely, pseurotin A, pseurotin A₂, pseurotin F1, 11-<i>O</i>-methylpseurotin A, pseurotin D, azaspirofuran A, and azaspirofuran B, were isolated from the bioactive marine fungus <i>Aspergillus fumigatus</i>, and their antiseizure activity was evaluated in the larval zebrafish pentylenetetrazole (PTZ) seizure model. Pseurotin A₂ and azaspirofuran A were identified as antiseizure hits, while their close chemical analogues were inactive. Besides, electrophysiological analysis from the zebrafish midbrain demonstrated that pseurotin A₂ and azaspirofuran A also ameliorate PTZ-induced epileptiform discharges. Next, to determine whether these findings translate to mammalians, both compounds were analyzed in the mouse 6 Hz (44 mA) psychomotor seizure model. They lowered the seizure duration dose-dependently, thereby confirming their antiseizure properties and suggesting activity against drug-resistant seizures. Finally, in a thorough ADMET assessment, pseurotin A₂ and azaspirofuran A were found to be drug-like. Based on the prominent antiseizure activity in both species and the drug-likeness, we propose pseurotin A₂ and azaspirofuran A as lead compounds that are worth further investigation for the treatment of epileptic seizures. This study not only provides the first evidence of antiseizure activity of pseurotins and azaspirofurans, but also demonstrates the value of the zebrafish model in (marine) natural product drug discovery in general, and for ASD discovery in particular

Chaxapeptin, a Lasso Peptide from Extremotolerant <i>Streptomyces leeuwenhoekii</i> Strain C58 from the Hyperarid Atacama Desert

Lasso peptides are ribosomally synthesized and post-translationally modified peptides (RiPPs) that possess a unique “lariat knot” structural motif. Genome mining-targeted discovery of new natural products from microbes obtained from extreme environments has led to the identification of a gene cluster directing the biosynthesis of a new lasso peptide, designated as chaxapeptin <b>1</b>, in the genome of <i>Streptomyces leeuwenhoekii</i> strain C58 isolated from the Atacama Desert. Subsequently, <b>1</b> was isolated and characterized using high-resolution electrospray ionization mass spectrometry and nuclear magnetic resonance methods. The lasso nature of <b>1</b> was confirmed by calculating its nuclear Overhauser effect restraint-based solution structure. Chaxapeptin <b>1</b> displayed a significant inhibitory activity in a cell invasion assay with human lung cancer cell line A549