Structure elucidation of bioactive natural products from Madagascar marine algae and cyanobacteria

This thesis is an investigation of the natural products deriving from marine algae and cyanobacteria and has resulted in the discovery of eleven new secondary metabolites. The structure elucidations of these new molecules were performed using a variety of spectroscopic techniques. Four new macrolides were isolated and characterized from the Madagascar marine cyanobacterium Geitlerinema sp. These ankaraholides are structurally similar to the potently cytotoxic swinholides and were found to have cytotoxicities ranging from 178 nM to 354 nM against human lung cancer (NCI-H460) and mouse neuro-2a cell lines. Since swinholide-type compounds were previously localized to the heterotrophic bacteria of sponges, these findings raise intriguing questions about their true metabolic source. Geitlerinema sp. was found to be particularly rich in chemistry, and also produced the new linear lipopeptide mitsoamide with unusual structural features including an aminal moiety, a homolysine residue and a polyketide unit (3,7- dimethoxy-5-methyl- nonanedioic acid) (DMNA). A collection of the red marine alga Portieria hornemannii from the south of Madagascar (Tolagniaro, Fort Dauphin), led to the isolation of the previously reported halogenated monoterpene, halomon, and the discovery of three new related metabolites. These molecules were found to inhibit DNA methyltransferase 1 (DNMT-1). As a result of efforts to identify bioactive agents from the marine cyanobacterium Lyngbya majuscula, tanikolide dimer, a novel SIRT2 inhibitor (IC50 = 176 nM), and tanikolide seco-acid were isolated. The depside molecular structure of tanikolide dimer, which is likely a meso compound, was established by NMR, MS and chiral HPLC analyses. The structure of tanikolide dimer raises a number of intriguing configurational and biosynthetic questions for further study. The bioassay guided fractionation of a collection of the brown marine alga Dictyota sp. from Netherland Antilles Playa Fort, led to the identification of a novel HDAC inhibitor with a dolastane carbon skeleton. The novel molecule was also found to possess antimalarial activity. Other known HDAC inhibitors with interesting antimalarial activity have been reported previously, and based on this efficacy against malaria, HDAC appears to be a viable target for the development of antiparasitic agents.Keywords: structure elucidation, linear peptide, macrolactone, bioactive natural products, cyanobacteria, macrolide, piperidine amine, diterpene, halogenated monoterpene, marine natural product

The chaos in calibrating crop models

Calibration, the estimation of model parameters based on fitting the model to experimental data, is among the first steps in many applications of system models and has an important impact on simulated values. Here we propose and illustrate a novel method of developing guidelines for calibration of system models. Our example is calibration of the phenology component of crop models. The approach is based on a multi-model study, where all teams are provided with the same data and asked to return simulations for the same conditions. All teams are asked to document in detail their calibration approach, including choices with respect to criteria for best parameters, choice of parameters to estimate and software. Based on an analysis of the advantages and disadvantages of the various choices, we propose calibration recommendations that cover a comprehensive list of decisions and that are based on actual practices.HighlightsWe propose a new approach to deriving calibration recommendations for system modelsApproach is based on analyzing calibration in multi-model simulation exercisesResulting recommendations are holistic and anchored in actual practiceWe apply the approach to calibration of crop models used to simulate phenologyRecommendations concern: objective function, parameters to estimate, software usedCompeting Interest StatementThe authors have declared no competing interest

Mode of Action of Diterpene and Characterization of Related Metabolites from the Soft Coral, Xenia elongata

Chemical and biological investigation of the cultured marine soft coral Xenia elongata led to the isolation of two new diterpenes (2, 3). Their structures were elucidated using a combination of NMR and mass spectrometry. Biological evaluations and assessments were determined using the specific apoptosis induction assay based on genetically engineered mammalian cell line D3 deficient in Bak and Bax and derived from a mouse epithelial cell. The diterpenes induce apoptosis in low micromolar concentrations. The results indicate that the previously isolated compound (1) affects cell in a manner similar to that of HSP90 and HDAC inhibitors and in a manner opposite of PI3 kinase/mTOR inhibitors. Compound (3) inhibits selectively HDAC6 in high micromolar concentrations

Ammonificins C and D, Hydroxyethylamine Chromene Derivatives from a Cultured Marine Hydrothermal Vent Bacterium, Thermovibrio ammonificans

Chemical and biological investigation of the cultured marine hydrothermal vent bacterium, Thermovibrio ammonifican led to the isolation of two hydroxyethylamine chromene derivatives, ammonificins C and D. Their structures were elucidated using combination of NMR and mass spectrometry. Absolute stereochemistry was ascertained by comparison of experimental and calculated CD spectra. Biological evaluation and assessment were determined using the patented ApopScreen cell-based screen for apoptosis-induction. Ammonificins C and D induce apoptosis in micromolar concentrations. To our knowledge, this finding is the first report of chemical compounds that induce apoptosis from the cultured deep-sea marine organism, hydrothermal vent bacterium, Thermovibrio ammonificans

Urinary tract infection in diabetics hospitalized in Befelatanana Hospital, Antananarivo: Epidemiological, clinical, biological profiles and risk factors for multidrug‐resistant bacterial infection

Key Clinical Message The main type of urinary tract infection in hospitalized diabetics in Antananarivo is acute pyelonephritis; Escherichia coli is the most isolated uropathogen; imipenem, amikacin, fosfomycin and ceftriaxone are the major antibiotics for which Escherichia coli retain good sensitivity; Type 2 diabetes is predictive factor for infection by multidrug resistant bacteria. Abstract This study aimed to describe the epidemiological‐clinical profiles of diabetics hospitalized for bacterial urinary tract infections in the Endocrinology Department of Befelatanana Hospital, to identify the main bacteria responsible, their antibiotic sensitivity profile and the factors associated with multidrug‐resistant bacterial infection. A cross‐sectional study was conducted between March 2017 and March 2020 involving all diabetics hospitalized for documented community‐acquired bacterial urinary tract infection during this period. The hospital prevalence of urinary tract infections was 4.64%. The mean age of the patients was 59.06 ± 14.26 years and the sex ratio was 0.15. The main sign was fever (55.76%). The main clinical form was uncomplicated acute pyelonephritis (38.46%). Fifty‐seven bacterial uropathogens were isolated. The most frequent was Escherichia coli (77.19%). Escherichia coli was sensitive to ertapenem and nitrofurantoin in 100% of cases, to Amikacin in 97.5% of cases, to Fosfomycin in 94.4% of cases and to Ceftriaxone in 80.65% of cases. Thirteen patients were infected with multidrug‐resistant bacteria, all of them are extended‐spectrum beta‐lactamase‐producing Enterobacteriaceae. Only the type of diabetes was associated with multidrug‐resistant bacteria infection. The epidemiological‐clinical and biological characteristics of urinary tract infections in our diabetics are similar to those reported in the literature. Compliance with the rules of proper antibiotic use is imperative to limit the emergence and spread of multidrug‐resistant bacteria