Pain relief and pain intensity response to GLP-1 receptor agonist ROSE-010 in irritable bowel syndrome; clinical study cross-analysis with respect to patient characteristics.

Background And Aims: Glucagon-like peptide-1 receptor agonist ROSE-010 has been studied for management of irritable bowel syndrome (IBS). ROSE-010 showed promising effects by reducing pain during attacks of IBS. In this exploratory substudy, we cross-analyzed earlier data to identify the most suitable subpopulation for treatment with ROSE-010.

A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy.

Background & Aims: Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis.

GR3027 reversal of neurosteroid-induced, GABA-A receptor-mediated inhibition of human brain function: an allopregnanolone challenge study.

Rationale: GR3027 is a novel small molecule GABA-A receptor-modulating steroid antagonist, which in non-clinical studies has shown promise for treatment of human disorders due to allosteric over-activation of GABA-A receptors by neurosteroids, such as allopregnanolone. We here studied its safety, pharmacokinetics, and ability to inhibit allopregnanolone effects in humans.

Methods: Safety and pharmacokinetics were studied in healthy adult males receiving ascending single or multiple oral GR3027 vs.

PanViz: interactive visualization of the structure of functionally annotated pangenomes.

Summary: PanViz is a novel, interactive, visualization tool for pangenome analysis. PanViz allows visualization of changes in gene group (groups of similar genes across genomes) classification as different subsets of pangenomes are selected, as well as comparisons of individual genomes to pangenomes with gene ontology based navigation of gene groups. Furthermore it allows for rich and complex visual querying of gene groups in the pangenome.

Production of the Bioactive Compounds Violacein and Indolmycin Is Conditional in a Mutant of S4054 Lacking the Malic Enzyme.

It has previously been reported that some strains of the marine bacterium produce the purple bioactive pigment violacein as well as the antibiotic compound indolmycin, hitherto only found in . The purpose of the present study was to determine the relative role of each of these two compounds as antibacterial compounds in S4054. Using Tn transposon mutagenesis, a mutant strain that was significantly reduced in violacein production in mannose-containing substrates was created.

Accurate dereplication of bioactive secondary metabolites from marine-derived fungi by UHPLC-DAD-QTOFMS and a MS/HRMS library.

In drug discovery, reliable and fast dereplication of known compounds is essential for identification of novel bioactive compounds. Here, we show an integrated approach using ultra-high performance liquid chromatography-diode array detection-quadrupole time of flight mass spectrometry (UHPLC-DAD-QTOFMS) providing both accurate mass full-scan mass spectrometry (MS) and tandem high resolution MS (MS/HRMS) data. The methodology was demonstrated on compounds from bioactive marine-derived strains of Aspergillus, Penicillium, and Emericellopsis, including small polyketides, non-ribosomal peptides, terpenes, and meroterpenoids.

Draft Genome Sequence of Photobacterium halotolerans S2753, Producer of Bioactive Secondary Metabolites.

We report here the whole draft genome sequence of marine isolate Photobacterium halotolerans S2753, which produces the known antibiotic holomycin and also ngercheumicins and solonamides A and B, which interfere with virulence of methicillin-resistant Staphylococcus aureus strains by interacting with the quorum-sensing system.

Solonamide B inhibits quorum sensing and reduces Staphylococcus aureus mediated killing of human neutrophils.

Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a serious human pathogen, and particularly the spread of community associated (CA)-MRSA strains such as USA300 is a concern, as these strains can cause severe infections in otherwise healthy adults. Recently, we reported that a cyclodepsipeptide termed Solonamide B isolated from the marine bacterium, Photobacterium halotolerans strongly reduces expression of RNAIII, the effector molecule of the agr quorum sensing system. Here we show that Solonamide B interferes with the binding of S.

Identification of four new agr quorum sensing-interfering cyclodepsipeptides from a marine Photobacterium.

During our search for new natural products from the marine environment, we discovered a wide range of cyclic peptides from a marine Photobacterium, closely related to P. halotolerans. The chemical fingerprint of the bacterium showed primarily non-ribosomal peptide synthetase (NRPS)-like compounds, including the known pyrrothine antibiotic holomycin and a wide range of peptides, from diketopiperazines to cyclodepsipeptides of 500-900 Da.

Toxicity of bioactive and probiotic marine bacteria and their secondary metabolites in Artemia sp. and Caenorhabditis elegans as eukaryotic model organisms.

We have previously reported that some strains belonging to the marine Actinobacteria class, the Pseudoalteromonas genus, the Roseobacter clade, and the Photobacteriaceae and Vibrionaceae families produce both antibacterial and antivirulence compounds, and these organisms are interesting from an applied point of view as fish probiotics or as a source of pharmaceutical compounds. The application of either organisms or compounds requires that they do not cause any side effects, such as toxicity in eukaryotic organisms. The purpose of this study was to determine whether these bacteria or their compounds have any toxic side effects in the eukaryotic organisms Artemia sp.

Nigribactin, a novel siderophore from Vibrio nigripulchritudo, modulates Staphylococcus aureus virulence gene expression.

Staphylococcus aureus is a serious human pathogen that employs a number of virulence factors as part of its pathogenesis. The purpose of the present study was to explore marine bacteria as a source of compounds that modulate virulence gene expression in S. aureus.

Gene sequence based clustering assists in dereplication of Pseudoalteromonas luteoviolacea strains with identical inhibitory activity and antibiotic production.

Some microbial species are chemically homogenous, and the same secondary metabolites are found in all strains. In contrast, we previously found that five strains of P. luteoviolacea were closely related by 16S rRNA gene sequence but produced two different antibiotic profiles.

Effect of a glucagon-like peptide 1 analog, ROSE-010, on GI motor functions in female patients with constipation-predominant irritable bowel syndrome.

The glucagon-like peptide 1 (GLP-1) analog ROSE-010 reduced pain during acute exacerbations of irritable bowel syndrome (IBS). Our objective was to assess effects of ROSE-010 on several gastrointestinal (GI) motor and bowel functions in constipation-predominant IBS (IBS-C). In a single-center, randomized, parallel-group, double-blind, placebo-controlled, dose-response study, we evaluated safety, pharmacodynamics, and pharmacokinetics in female patients with IBS-C.

Inhibition of virulence gene expression in Staphylococcus aureus by novel depsipeptides from a marine photobacterium.

During a global research expedition, more than five hundred marine bacterial strains capable of inhibiting the growth of pathogenic bacteria were collected. The purpose of the present study was to determine if these marine bacteria are also a source of compounds that interfere with the agr quorum sensing system that controls virulence gene expression in Staphylococcus aureus. Using a gene reporter fusion bioassay, we recorded agr interference as enhanced expression of spa, encoding Protein A, concomitantly with reduced expression of hla, encoding α-hemolysin, and rnaIII encoding RNAIII, the effector molecule of agr.

Wide distribution of closely related, antibiotic-producing Arthrobacter strains throughout the Arctic Ocean.

We isolated 16 antibiotic-producing bacterial strains throughout the central Arctic Ocean, including seven Arthrobacter spp. with almost identical 16S rRNA gene sequences. These strains were numerically rare, as revealed using 454 pyrosequencing libraries.

Production of bioactive secondary metabolites by marine vibrionaceae.

Bacteria belonging to the Vibrionaceae family are widespread in the marine environment. Today, 128 species of vibrios are known. Several of them are infamous for their pathogenicity or symbiotic relationships.

Dereplication of microbial natural products by LC-DAD-TOFMS.

Dereplication, the rapid identification of known compounds present in a mixture, is crucial to the fast discovery of novel natural products. Determining the elemental composition of compounds in mixtures and tentatively identifying natural products using MS/MS and UV/vis spectra is becoming easier with advances in analytical equipment and better compound databases. Here we demonstrate the use of LC-UV/vis-MS-based dereplication using data from UV/vis diode array detection and ESI+/ESI- time-of-flight MS for assignment of 719 microbial natural product and mycotoxin reference standards.

Chitin stimulates production of the antibiotic andrimid in a Vibrio coralliilyticus strain.

Vibrio coralliilyticus is a putative coral pathogen in tropical oceans, but also possesses antagonistic traits. We previously reported antibacterial activity in Vibrio coralliilyticus strain S2052 based upon the antibiotic andrimid. The purpose of the present study was to determine whether V.

Antibacterial compounds from marine Vibrionaceae isolated on a global expedition.

On a global research expedition, over 500 bacterial strains inhibitory towards pathogenic bacteria were isolated. Three hundred of the antibacterial strains were assigned to the Vibrionaceae family. The purpose of the present study was to investigate the phylogeny and bioactivity of five Vibrionaceae strains with pronounced antibacterial activity.

Bioactivity, chemical profiling, and 16S rRNA-based phylogeny of Pseudoalteromonas strains collected on a global research cruise.

One hundred one antibacterial Pseudoalteromonas strains that inhibited growth of a Vibrio anguillarum test strain were collected on a global research cruise (Galathea 3), and 51 of the strains repeatedly demonstrated antibacterial activity. Here, we profile secondary metabolites of these strains to determine if particular compounds serve as strain or species markers and to determine if the secondary metabolite profile of one strain represents the bioactivity of the entire species. 16S rRNA gene similarity divided the strains into two primary groups: One group (51 strains) consisted of bacteria which retained antibacterial activity, 48 of which were pigmented, and another group (50 strains) of bacteria which lost antibacterial activity upon sub-culturing, two of which were pigmented.

Explorative solid-phase extraction (E-SPE) for accelerated microbial natural product discovery, dereplication, and purification.

Microbial natural products (NP) cover a high chemical diversity, and in consequence extracts from microorganisms are often complex to analyze and purify. A distribution analysis of calculated pK(a) values from the 34390 records in Antibase2008 revealed that within pH 2-11, 44% of all included compounds had an acidic functionality, 17% a basic functionality, and 9% both. This showed a great potential for using ion-exchange chromatography as an integral part of the separation procedure, orthogonal to the classic reversed-phase strategy.

Isolation and NMR characterization of fumonisin B2 and a new fumonisin B6 from Aspergillus niger.

A new fumonisin, fumonisin B(6) (1), has been isolated by cation-exchange and reverse-phase chromatography, together with fumonisin B(2) (2), from stationary cultures of the fungus Aspergillus niger NRRL 326. Analysis of mass spectrometric and NMR data determined that FB(6) is a positional isomer of FB(1) and iso-FB(1), having hydroxyl functions at C3, C4, and C5. Analysis of the NMR data for FB(2) showed very similar chemical shift values when compared to an authentic Fusarium FB(2) standard, strongly indicating identical molecules despite that an absolute stereochemical assignment of FB(2) from A.