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Facultat de Farmàcia
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Edifici A - Primer pis

Avinguda Joan XXIII s/n
08028 - Barcelona
Telèfon: 93 402 1093
Fax: 93 403 1886

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A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

Francesc Rabanal, Ariadna Grau-Campistany, Xavier Vila-Farrés, Javier González-Linares, Miquel Borràs, Jordi Vila, Ángeles Manresa, Yolanda Cajal*

* Departament de Fisicoquímica

Abstract: Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrugresistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.

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Easy access to (2-imidazolin-4-yl)phosphonates by a microwave assisted multicomponent reaction

Sonia Abàs, Carolina Estarellas, F.Javier Luque, Carmen Escolano*

* Departament de Farmacologia i Química Terapèutica, Unitat de Química Orgànica

Abstract: An efficient and user-friendly synthetic process involving the combination of multicomponent reaction methodology and microwave heating generates unprecedented (2-imidazolin-4-yl)phosphonates 1-18. This strategy presents a silver-catalysed, operationally simple and environmentally friendly transformation without the need of anhydrous atmosphere or additional solvents.

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Outer-inner membrane vesicles naturally secreted by Gram-negative pathogenic bacteria

Carla Pérez-Cruz, Lidia Delgado, Carmen López-Iglesias, E. Mercadé*

* Departament de Microbiologia i Parasitologia Sanitàries, Unitat de Microbiologia

Abstract: Outer-inner membrane vesicles (O-IMVs) were recently described as a new type of membrane vesicle secreted by the Antarctic bacterium Shewanella vesiculosa M7T. Their formation is characterized by the protrusion of both outer and plasma membranes, which pulls cytoplasmic components into the vesicles. To demonstrate that this is not a singular phenomenon in a bacterium occurring in an extreme environment, the identification of O-IMVs in pathogenic bacteria was undertaken. With this aim, a structural study by Transmission Electron Microscopy (TEM) and Cryo-transmission electron microscopy (Cryo-TEM) was carried out, confirming that O-IMVs are also secreted by Gram-negative pathogenic bacteria such as Neisseria gonorrhoeae , Pseudomonas aeruginosa PAO1 and Acinetobacter baumannii AB41, in which they represent between 0.23% and 1.2% of total vesicles produced. DNA and ATP, which are components solely found in the cell cytoplasm, were identified within membrane vesicles of these strains. The presence of DNA inside the O-IMVs produced by N. gonorrhoeae was confirmed by gold DNA immunolabeling with a specific monoclonal IgM against double-stranded DNA. A proteomic analysis of N. gonorrhoeae -derived membrane vesicles identified proteins from the cytoplasm and plasma membrane. This confirmation of O-IMV extends the hitherto uniform definition of membrane vesicles in Gram-negative bacteria and explains the presence of components in membrane vesicles such as DNA, cytoplasmic and inner membrane proteins, as well as ATP, detected for the first time. The production of these O-IMVs by pathogenic Gram-negative bacteria opens up new areas of study related to their involvement in lateral gene transfer, the transfer of cytoplasmic proteins, as well as the functionality and role of ATP detected in these new vesicles .

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A novel pathway producing dimethylsulphide in bacteria is widespread in soil environments

O. Carrión, A.R.J. Curson, D. Kumaresan, Y. Fu, A.S. Lang, E. Mercadé*, J.D. Tood

* Departament de Microbiologia i Parasitologia Sanitàries, Unitat de Microbiologia

Abstract: The volatile compound dimethylsulphide (DMS) is important in climate regulation, the sulphur cycle and signalling to higher organisms. Microbial catabolism of the marine osmolyte dimethylsulphoniopropionate (DMSP) is thought to be the major biological process generating DMS. Here we report the discovery and characterization of the first gene for DMSP-independent DMS production in any bacterium. This gene, mddA , encodes a methyltransferase that methylates methanethiol and generates DMS. MddA functions in many taxonomically diverse bacteria including sediment-dwelling pseudomonads, nitrogen-fixing bradyrhizobia and cyanobacteria, and mycobacteria including the pathogen Mycobacterium tuberculosis . The mddA gene is present in metagenomes from varied environments, being particularly abundant in soil environments, where it is predicted to occur in up to 76% of bacteria. This novel pathway may significantly contribute to global DMS emissions, especially in terrestrial environments and could represent a shift from the notion that DMSP is the only significant precursor of DMS.

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Improved design of PPRHs for gene silencing

Laura Rodríguez, Xenia Villalobos, Anna Solé, Carolina Lliberos, Carlos J. Ciudad, and Véronique Noé*

* Departament de Bioquímica i Biologia Molecular

Abstract: Nowadays , the modulation of gene expression by nucleic acids has become a routine tool in Biomedical research for target validation and it is also used to develop new therapeutic approaches. Recently, we developed the so-called Polypurine Reverse Hoogsteen hairpins (PPRHs) that show high stability and a low immunogenic profile and we demonstrated their efficacy both in vitro and in vivo . In this work, we explored different characteristics of PPRHs to improve their usage as a tool for gene silencing. We studied the role of PPRH length in the range from 20 to 30 nucleotides. We also proved their higher affinity of binding and efficacy on cell viability compared to non-modified TFOs. To overcome possible off-target effects, we tested Wild-type PPRHs, which proved to be capable of binding to their target sequence with more affinity, displaying a higher stability of binding and a higher effect in terms of cell viability. Moreover, we developed a brand new molecule called Wedge-PPRH with the ability to lock the ds-DNA into the displaced structure and proved its efficacy in prostate and breast cancer cell lines.

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Repair of single-point mutations by polypurine reverse Hoogsteen hairpins

Anna Solé, Xenia Villalobos, Carlos J. Ciudad, * and Véronique Noé

* Departament de Bioquímica i Biologia Molecular

Abstract: Polypurine reverse Hoogsteen hairpins (PPRHs) are formed by two intramolecularly bound antiparallel homopurine domains linked by a five-thymidine loop. One of the homopurine strands binds with antiparallel orientation by Watson-Crick bonds to the polypyrimidine target sequence, forming a triplex. We had previously reported the ability of PPRHs to effectively bind dsDNA displacing the fourth strand away from the newly formed triplex. The main goal of this work was to explore the possibility of repairing a point mutation in mammalian cells using PPRHs as tools. These repair-PPRHs contain different combinations of extended sequences of DNA with the corrected nucleotide to repair the point mutation. As a model we used the dihydrofolate reductase gene. On the one hand, we demonstrate in vitro that PPRHs bind specifically to their polypyrimidine target sequence, opening the two strands of the dsDNA, and allowing the binding of a given repair oligonucleotide to the displaced strand of the DNA. Subsequently, we show at a cellular level (Chinese ovary hamster cells) that repair-PPRHs are able to correct a single-point mutation in a dihydrofolate reductase minigene bearing a nonsense mutation, both in an extrachromosomal location and when the mutated plasmid was stably transfected into the cells. Finally, this methodology was successfully applied to repair a single-point mutation at the endogenous locus, using the DA5 cell line with a deleted nucleotide in exon six of the dhfr gene.

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Analysis of a plant complex resistance gene locus underlying immune-related hybrid incompatibility and its occurrence in nature

Rubén Alcázar,* Marcel von Reth, Jaqueline Bautor, Eunyoung Chae, Detlef Wigel, Maarten Koornneef, Jane E. Parker

* Departament de Productes Naturals, Biologia Vegetal i Edafologia, Unitat de Fisiologia Vegetal

Abstract: Mechanisms underlying speciation in plants include detriment al (incompatible) genetic interactions between parental alleles that incur a fitness cost in hybrids. We reported on recessive hybrid incompatibility between an Arabidopsis thaliana strain from Poland, Landsberg erecta (L er ), and many Central Asian A. thaliana strains. The incompatible interaction is determined by a polymorphic cluster of Toll/interleukin-1 receptor-nucleotide binding-leucine rich repeat (TNL) RPP1 ( Recognition of Peronospora parasitica1 )-like genes in L er and alleles of the receptor-like kinase Strubbelig Receptor Family 3 ( SRF3 ) in Central Asian strains Kas-2 or Kond, causing temperature-dependent autoimmunity and loss of growth and reproductive fitness. Here, we genetically dissected the RPP1 -like L er locus to determine contributions of individual RPP1 -like L er ( R1–R8 ) genes to the incompatibility. In a neutral background, expression of most RPP1 -like L er genes, except R3 , has no effect on growth or pathogen resistance. Incompatibility involves increased R3 expression and engineered R3 overexpression in a neutral background induces dwarfism and sterility. However, no individual RPP1 -like Ler gene is sufficient for incompatibility between L er and Kas-2 or Kond, suggesting that co-action of at least two RPP1 -like membres underlies this epistatic interaction. We find that the RPP1 -like L er haplotype is frequent and occurs with other L er RPP1 -like alleles in a local population in Gorzów Wielkopolski (Poland). Only Gorzów individuals carrying the RPP1 -like L er haplotype are incompatible with Kas-2 and Kond, whereas other RPP1 -like alleles in the population are compatible. Therefore, the RPP1 -like Ler haplotype has been maintained in genetically different individuals at a single site, allowing exploration of forces shaping the evolution of RPP1 -like genes at local and regional population scales.

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Long-term anaerobic digestion of microalgae grown in HRAP for wastewater treatment. Effect of microwave pretreatment

Fabiana Passos, Mariona Hernández-Mariné*, Joan García, Ivet Ferrer

* Departament de Productes Naturals, Biologia Vegetal i Edafologia, Unitat de Botànica

Abstract: This paper describes the anaerobic digestion of microalgal biomass from high rate ponds in continuous anaerobic reactors for biogas production. With hydraulic retention times (HRT) of 15 and 20 days, the volatile solids (VS) removal did not exceed 30%, and the methane production rate ranged between 0.12 and 0.14 L CH4/L day. To improve process performance, microwave irradiation at 900 W for 3 min (specific energy ca. 70,000 kJ/kg VS) was applied as a pretreatment step. The VS removal increased to 40 and 45% at 15 and 20 days HRT, respectively. Consequently, the methane production rate increased to 0.16 and 0.20 L CH4/L day at 15 and 20 days HRT, respectively. Microscopic analysis confirmed cell wall damage, although generally without lysis, after irradiating microalgal biomass. However, the energy consumption was much higher than the extra energy production of the process. Indeed, microalgal biomass should not only be thickened but also dewatered if microwave irradiation was to be applied as a pretreatment to anaerobic digestion for biogas production.

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The freshwater alga Chroothece richteriana (Rhodophyta) as a potential source of lipids

Marina Aboal, Daniel González-Silveria, Mónica Roldán, Mariona Hernández-Mariné*, José Ángel López-Jiménez, Brian A. Whitton

* Departament de Productes Naturals, Biologia Vegetal i Edafologia, Unitat de Botànica

Abstract: During an ecological study of Chroothece (Rhodophyta) in a small river in a semi-arid region of south-east Spain it became clear that most of these cells had a high lipid content. This suggested potential uses in biotechnology, which has been investigated further. The colonies, which occur in full sunlight, are typically orange-brown. Most, perhaps all, the yellow-orange colour is associated with their high carotenoid content, with the carotenoid to chlorophyll ratio up to 2.7. The polyunsaturated fatty acyl composition of the glycerides was 35.3% of the dry weight. This consisted mainly of omega-3 (5.9%) and omega-6 (29.4%) fats. The relatively high proportion of docosahexaenoyl (1.78%), eicosapentaenoyl (14.15%), arachidonoyl (0.92%) and gamma-linolenoyl (0.78%) suggests use for medical and dietary purposes. All cells have a high phycocyanin content whilst phycoerythrin is absent. The alga has a wide distribution globally and hence provides scope for selecting strains with optimum properties.

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New and poorly known coccoid species (Cyanoprokaryota) from the mid-depth and deep epilithon of a carbonate mountain lake

Marco Canotani, Jiri Komárek, Mariona Hernández-Mariné*, and Nicola Angeli

* Departament de Productes Naturals, Biologia Vegetal i Edafologia, Unitat de Botànica

Abstract: The deep littoral zone hosts a unique but understudied subset of lake periphyton. We investigated epilithic cyanoprokaryotes in a carbonate meromictic lake (Lake Tovel, southeastern Alps) to obtain information on 2 poorly known, deep-dwelling coccoid species (one new to science) and to analyze their distribution in light of the current understanding of the depth distribution of lake periphyton. Cyanoprokaryotes in Lake Tovel have distinct depth distributions among 3 zones: shallow (0-4 m), mid-depth (6-12 m), and deep (15-24 m). The mid-depth and deep zones are characterized by high stability with favorable growth conditions and by severe light limitation, respectively. Both zones have unique taxa that frequently possess colorless sheaths or pink-red-violet cell contents. The 2 most poorly known cyanoprokaryotes found in Lake Tovel (both pink-red-violet) were a species of Geitleribactron new to science ( Geitleribactron purpureum sp. nov. Cantonati et Komárek) and the rare Chlorogloea purpurea . We described and documented, respectively, these 2 species by means of light microscopy, careful comparison with the most-similar morphospecies, transmission electron microscopy (TEM), and ecological characteristics. We are the first to describe the TEM ultrastructure of a Chlorogloea species and to characterize the autecology and distribution of C. purpurea , which, in spite of its very specific habitat requirements (deep waters of carbonate oligotrophic mountain lakes), has been reported in several studies from disparate habitats and geographic locations.

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The ortho-substituent effect on the Ag-catalysed decarboxylation of bezoic acids

Rachel Grainger, Josep Cornella, David C. Blakemore, Igor Larrosa and Josep M. Campanera*

* Departament de Fisicoquímica

Abstract: A combined experimental and computational investigation on the Ag-catalysed decarboxylation of benzoic acids is reported herein. The present study demonstrates that a substituent at the ortho position exerts dual effects in the decarboxylation event. On one hand, ortho-substituted benzoic acids are inherently destabilised starting materials compared to their meta- and para-substituted counterparts. On the other hand, the presence of an ortho-electron-withdrawing group results in an additional stabilisation of the transition state. The combination of both effects results in an overall reduction of the activation energy barrier associated with the decarboxylation event. Furthermore, the Fujita-Nishioka linear free energy relationship model indicates that steric bulk of the substituent can also exert a negative effect by destabilising the transition state of decarboxylation.

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  © Universitat de Barcelona Edició: Secretaria d'Estudiants i Docència Facultat de Farmàcia
Última actualització o validació:08.07.2015