3 research outputs found
Dermacozines HāJ 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 10ā898 m. The fermentation process using complex
media led to the production of three new pigmented heteroaromatic
(oxidized and reduced) phenazine compounds, dermacozines HāJ
(<b>1</b>ā<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 IC<sub>50</sub> value of 18.8 Ī¼M
Zebrafish-Based Discovery of Antiseizure Compounds from the Red Sea: Pseurotin A<sub>2</sub> 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 Ī³-lactams, namely, pseurotin
A, pseurotin A<sub>2</sub>, 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 A<sub>2</sub> 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 A<sub>2</sub> 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 A<sub>2</sub> 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 A<sub>2</sub> 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 ālariat knotā
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