Antimicrobial Activity of Securamines From the Bryozoan Securiflustra securifrons

Natural products and their derivatives have served as powerful therapeutics against pathogenic microorganisms and are the mainstay of our currently available treatment options to combat infections. As part of our ongoing search for antimicrobial natural products from marine organisms, one fraction prepared from the Arctic marine bryozoan Securiflustra securifrons was found to be active against the human pathogenic bacterium Streptococcus agalactiae (gr. B). Chemical investigation of the fraction revealed that it contained several variants of the highly modified secondary metabolites known as securamines. The securamines are alkaloids sharing a common isoprene-histamine-tryptamine backbone. In this study, we describe the antimicrobial activities of securamine C, E, and H – J (4, 5, and 1-3) and the attempt to deconvolute the mode of action of 1

The bromotyrosine derivative Ianthelline isolated from the Arctic marine sponge Stryphnus fortis inhibits marine micro- and macrobiofouling

International audienceThe inhibition of marine biofouling by the bromotyrosine derivative ianthelline, isolated from the Arctic marine sponge Stryphnus fortis, is described. All major stages of the fouling process are investigated. The effect of ianthelline on adhesion and growth of marine bacteria and microalgae is tested to investigate its influence on the initial microfouling process comparing with the known marine antifoulant barettin as a reference. Macrofouling is studied via barnacle (Balanus improvisus) settlement assays and blue mussel (Mytilus edulis) phenoloxidase inhibition. Ianthelline is shown to inhibit both marine micro-and macrofoulers with a pronounced effect on marine bacteria (minimum inhibitory concentration (MIC) values 0.1-10 mu g/mL) and barnacle larval settlement (IC50= 3.0 mu g/mL). Moderate effects are recorded on M. edulis (IC50= 45.2 mu g/mL) and microalgae, where growth is more affected than surface adhesion. The effect of ianthelline is also investigated against human pathogenic bacteria. Ianthelline displayed low micromolar MIC values against several bacterial strains, both Gram positive and Gram negative, down to 2.5 mu g/mL. In summary, the effect of ianthelline on 20 different representative marine antifouling organisms and seven human pathogenic bacterial strains is presented

Lulworthinone, a New Dimeric Naphthopyrone From a Marine Fungus in the Family Lulworthiaceae With Antibacterial Activity Against Clinical Methicillin-Resistant Staphylococcus aureus Isolates

The emergence of drug-resistant bacteria is increasing rapidly in all parts of the world, and the need for new antibiotics is urgent. In our continuous search for new antimicrobial molecules from under-investigated Arctic marine microorganisms, a marine fungus belonging to the family Lulworthiaceae (Lulworthiales, Sordariomycetes, and Ascomycota) was studied. The fungus was isolated from driftwood, cultivated in liquid medium, and studied for its potential for producing antibacterial compounds. Through bioactivity-guided isolation, a novel sulfated biarylic naphtho-α-pyrone dimer was isolated, and its structure was elucidated by spectroscopic methods, including 1D and 2D NMR and HRMS. The compound, named lulworthinone (1), showed antibacterial activity against reference strains of Staphylococcus aureus and Streptococcus agalactiae, as well as several clinical MRSA isolates with MICs in the 1.56–6.25 μg/ml range. The compound also had antiproliferative activity against human melanoma, hepatocellular carcinoma, and non-malignant lung fibroblast cell lines, with IC50 values of 15.5, 27, and 32 μg/ml, respectively. Inhibition of bacterial biofilm formation was observed, but no eradication of established biofilm could be detected. No antifungal activity was observed against Candida albicans. During the isolation of 1, the compound was observed to convert into a structural isomer, 2, under acidic conditions. As 1 and 2 have high structural similarity, NMR data acquired for 2 were used to aid in the structure elucidation of 1. To the best of our knowledge, lulworthinone (1) represents the first new bioactive secondary metabolite isolated from the marine fungal order Lulworthiales

Two Novel Lyso-Ornithine Lipids Isolated from an Arctic Marine Lacinutrix sp. Bacterium

The Lacinutrix genus was discovered in 2005 and includes 12 Gram-negative bacterial species. To the best of our knowledge, the secondary metabolite production potential of this genus has not been explored before, and examination of Lacinutrix species may reveal novel chemistry. As part of a screening project of Arctic marine bacteria, the Lacinutrix sp. strain M09B143 was cultivated, extracted, fractionated and tested for antibacterial and cytotoxic activities. One fraction had antibacterial activity and was subjected to mass spectrometry analysis, which revealed two compounds with elemental composition that did not match any known compounds in databases. This resulted in the identification and isolation of two novel isobranched lyso-ornithine lipids, whose structures were elucidated by mass spectrometry and NMR spectroscopy. Lyso-ornithine lipids consist of a 3-hydroxy fatty acid linked to the alpha amino group of an ornithine amino acid through an amide bond. The fatty acid chains were determined to be iso-C15:0 (1) and iso-C16:0 (2). Compound 1 was active against the Gram-positive S. agalactiae, while 2 showed cytotoxic activity against A2058 human melanoma cells

Identification of New Purpuroine Analogues from the Arctic Echinodermata Pteraster militaris That Inhibit FLT3-ITD+ AML Cell Lines

Isolation of bioactive products from the marine environment is considered a very promising approach to identify new compounds that can be used for further drug development. In this work we have isolated three new compounds from the purpuroine family by mass-guided preparative HPLC; purpuroine K-M. These compounds where screened for antibacterial- and antifungal activity, antibiofilm formation and anti-cell proliferation activity. Additionally, apoptosis-, cell cycle-, kinase binding- and docking studies were performed to evaluate the mechanism-of-action. None of the compounds showed activity in antibacterial-, antibiofilm- or antifungal assays. However, one of the isolated compounds, purpuroine K, showed activity against two cell lines, MV-4-11 and MOLM-13, two AML cell lines both carrying the FTL3-ITD mutation. In MV-4-11 cells, purpuroine K was found to increase apoptosis and arrest cells cycle in G1/G0, which is a common feature of FLT3 inhibitors. Interactions between purpuroine K and the FLT3 wild type or FLT3 ITD mutant proteins could however not be elucidated in our kinase binding and docking studies. In conclusion, we have isolated three novel molecules, purpuroine K-M, one of which (purpuroine K) shows a potent activity against FLT3-ITD mutated AML cell lines, however, the molecular target(s) of purpuroine K still need to be further investigated

Identification of New Purpuroine Analogues from the Arctic Echinodermata Pteraster militaris That Inhibit FLT3-ITD+ AML Cell Lines

Isolation of bioactive products from the marine environment is considered a very promising approach to identify new compounds that can be used for further drug development. In this work we have isolated three new compounds from the purpuroine family by mass-guided preparative HPLC; purpuroine K-M. These compounds where screened for antibacterial- and antifungal activity, antibiofilm formation and anti-cell proliferation activity. Additionally, apoptosis-, cell cycle-, kinase binding- and docking studies were performed to evaluate the mechanism-of-action. None of the compounds showed activity in antibacterial-, antibiofilm- or antifungal assays. However, one of the isolated compounds, purpuroine K, showed activity against two cell lines, MV-4-11 and MOLM-13, two AML cell lines both carrying the FTL3-ITD mutation. In MV-4-11 cells, purpuroine K was found to increase apoptosis and arrest cells cycle in G1/G0, which is a common feature of FLT3 inhibitors. Interactions between purpuroine K and the FLT3 wild type or FLT3 ITD mutant proteins could however not be elucidated in our kinase binding and docking studies. In conclusion, we have isolated three novel molecules, purpuroine K-M, one of which (purpuroine K) shows a potent activity against FLT3-ITD mutated AML cell lines, however, the molecular target(s) of purpuroine K still need to be further investigated

Early radiologic signal of responsiveness to immune checkpoint blockade in microsatellite-stable/mismatch repair-proficient metastatic colorectal cancer

Background: Immune checkpoint blockade (ICB) results in radiologic tumour response dynamics that differ from chemotherapy efficacy measures and require an early signal of clinical utility. Methods: Previously untreated, unresectable microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) colorectal cancer (CRC) patients were randomly assigned to the oxaliplatin-based Nordic FLOX regimen (control arm) or repeat sequential two FLOX cycles and two ICB cycles (experimental arm). The radiologic response was assessed every 8 weeks. In this post hoc analysis, we explored early target lesion (TL) dynamics as indicator of ICB responsiveness. Progression-free survival (PFS) was the primary endpoint. Results: Using a landmark analysis approach, we categorised experimental-arm patients into ≥10% (N = 19) or <10% (N = 16) TL reduction at the first post-baseline response assessment. Median PFS for the groups was 16.0 (95% confidence interval (CI), 12.3–19.7) and 3.9 months (95% CI, 2.3–5.5), respectively, superior and inferior (both P < 0.01) to the median PFS of 9.8 months (95% CI, 4.9–14.7) for control arm patients (N = 31). Conclusions: Radiologic TL reduction of ≥10% at the first post-baseline response assessment identified patients with ICB-responsive metastatic MSS/pMMR-CRC. This pragmatic measure may be used to monitor patients in investigational ICB schedules, enabling early treatment adaptation for unresponsive cases.publishedVersio

The cost-effectiveness of opt-in and send-to-all HPV self-sampling among long-term non-attenders to cervical cancer screening in Norway : The Equalscreen randomized controlled trial

OBJECTIVE: We assessed the cost-effectiveness of mailing a human papillomavirus self-sampling (HPV-ss) kit, directly or via invitation to order, compared with mailing reminder letters among long-term non-attenders in Norway. METHODS: We conducted a secondary analysis using the Equalscreen study data with 6000 women aged 35-69 years who had not screened in 10+ years. Participants were equally randomized into three arms: reminder letter (control); invitation to order HPV-ss kit (opt-in); directly mailed HPV-ss kit (send-to-all). Cost-effectiveness (2020 Great British Pounds (GBP)) was estimated using incremental cost-effectiveness ratios (ICERs) per additional screened woman, and per additional cervical intraepithelial neoplasia grade 2 or worse (CIN2+) from extended and direct healthcare perspectives. RESULTS: Participation, CIN2+ detection, and total screening costs were highest in the send-to-all arm, followed by the opt-in and control arms. Non-histological physician appointments contributed to 67% of the total costs in the control arm and ≤ 31% in the self-sampling arms. From an expanded healthcare perspective, the ICERs were 135 GBP and 169 GBP per additional screened woman, and 2864 GBP and 4165 GBP per additional CIN2+ detected for the opt-in and send-to-all, respectively. CONCLUSIONS: Opt-in and send-to-all self-sampling were more effective and, depending on willingness-to-pay, may be considered cost-effective alternatives to improve screening attendance in Norway

Four new suomilides isolated from the cyanobacterium Nostoc sp. KVJ20 and proposal of their biosynthetic origin

The suomilide and the banyasides are highly modified and functionalized non-ribosomal peptides produced by cyanobacteria of the order Nostocales. These compound classes share several substructures, including a complex azabicyclononane core, which was previously assumed to be derived from the amino acid tyrosine. In our study we were able to isolate and determine the structures of four suomilides, named suomilide B – E (1–4). The compounds differ from the previously isolated suomilide A by the functionalization of the glycosyl group. Compounds 1–4 were assayed for anti-proliferative, anti-biofilm and anti-bacterial activities, but no significant activity was detected. The sequenced genome of the producer organism Nostoc sp. KVJ20 enabled us to propose a biosynthetic gene cluster for suomilides. Our findings indicated that the azabicyclononane core of the suomilides is derived from prephenate and is most likely incorporated by a proline specific non-ribosomal peptide synthetase-unit

The Myanmar Norway Environmental Programme’s Capacity building achievements

Prosjektleder: Ingrid NesheimThis report presents the key capacity building achievements resulting from the Myanmar Norway Environment Programme (2015-2018, and 2019-2023). The programme, a bilateral collaboration, between institutions of the Governments of Norway and Myanmar for improved environmental management enabled high achievement. The Programme included the following partners: In Myanmar, under MONREC, the Forest Department with the Watershed Management Division and the Nature and Wildlife Conservation Division, and the Environmental Conservation Department. In Norway, the Norwegian Environment Agency, NIVA and SINTEF. The Environmental Programme addressed the following topics, water Management, conservation of biodiversity, hazardous waste management and waste management on local level. The main activities and capacity building achievements from the four projects in the programme are presented.Norwegian embassy in Myanma