Fundacion MEDINA

La Línea de la Concepción, Spain

Fundacion MEDINA

La Línea de la Concepción, Spain
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De Pedro N.,Fundacion MEDINA | Cautain B.,Fundacion MEDINA | Melguizo A.,Fundacion MEDINA | Vicente F.,Fundacion MEDINA | And 2 more authors.
Journal of Bioenergetics and Biomembranes | Year: 2013

The development of new anti-neoplastic drugs is a key issue for cancer chemotherapy due to the reality that, most likely, certain cancer cells are resistant to current chemotherapy. The past two decades have witnessed tremendous advances in our understanding of the pathogenesis of cancer. These advances have allowed identification new targets as oncogenes, tumor supressor genes and the possible implication of the mitochondria (Fulda et al. Nat Rev Drug Discov 9:447-464, 2010). Annonaceous Acetogenins (ACGs) have been described as the most potent inhibitors of the respiratory chain because of their interaction with mitochondrial Complex I (Degli Esposti and Ghelli Biochim Biophys Acta 1187:116-120, 1994; Zafra-Polo et al. Phytochemistry 42:253-271, 1996; Miyoshi et al. Biochim Biophys Acta 1365:443-452, 1998; Tormo et al. Arch Biochem Biophys 369:119-126, 1999; Motoyama et al. Bioorg Med Chem Lett 12:2089-2092, 2002). To explore a possible application of natural products from Annonaceous plants to cancer treatment, we have selected four bis-tetrahydrofuranic ACGs, three from Annona cherimolia (cherimolin-1, motrilin and laherradurin) and one from Rollinia mucosa (rollinianstatin-1) in order to fully describe their mechanisms responsible within the cell (Fig. 1). In this study, using a hepato-carcinoma cell line (HepG2) as a model, we showed that the bis-THF ACGs caused cell death through the induction of the apoptotic mitochondrial pathway. Their potency and behavior were compared with the classical mitochondrial respiratory chain Complex I inhibitor rotenone in every apoptotic pathway step.[Figure not available: see fulltext.] © 2012 Springer Science+Business Media New York.

Sanchez-Hidalgo M.,Fundacion MEDINA | Montalban-Lopez M.,University of Granada | Cebrian R.,University of Granada | Valdivia E.,University of Granada | And 2 more authors.
Cellular and Molecular Life Sciences | Year: 2011

Bacteriocin AS-48 is an intriguing molecule because of its unique structural characteristics, genetic regulation, broad activity spectrum, and potential biotechnological applications. It was the first reported circular bacteriocin and has been undoubtedly the best characterized for the last 25 years. Thus, AS-48 is the prototype of circular bacteriocins (class IV), for which the structure and genetic regulation have been elucidated. This review discusses the state-of-the-art in genetic engineering with regard to this circular protein, with the use of site-directed mutagenesis and circular permutation. Mutagenesis studies have been used to unravel the role of (a) different residues in the biological activity, underlining the relevance of several residues involved in membrane interaction and the low correlation between stability and activity and (b) three amino acids involved in maturation, providing information on the specificity of the leader peptidase and the circularization process itself. To investigate the role of circularity in the stability and biological properties of the enterocin AS-48, two different ways of linearization have been attempted: in vitro by limited proteolysis experiments and in vivo by circular permutation in the structural gene as-48A. The results summarized here show the significance of circularization on the secondary structure, potency and, especially, the stability of AS-48 and point as well to a putative role of the leader peptide as a protecting moiety in the pre-proprotein. Taken all together, the data available on circular bacteriocins support the idea that AS-48 has been engineered by nature to make a remarkably active and stable protein with a broad spectrum of activity. © 2011 Springer Basel AG.

Montiel R.,INIA | Martin-Cabrejas I.,INIA | Langa S.,INIA | El Aouad N.,Fundacion MEDINA | And 3 more authors.
Food Microbiology | Year: 2014

Lactobacillus reuteri INIA P579 was used for the production and purification of reuterin. The purity of reuterin was assessed by high resolution electrospray ionization mass spectrometry (HRESIMS) and nuclear magnetic resonance (NMR) spectroscopy. After purification, reuterin concentration obtained was 1.3M. The inhibitory activity using Escherichia coli K12 as indicator strain was estimated to be 510 AU/ml. Survival curves in tryptic soy broth revealed that reuterin required to inhibit the growth of three Listeria monocytogenes strains was in the range of 2-4 AU/ml. Purified reuterin (10 AU/g) significantly reduced the growth of L.monocytogenes in cold-smoked salmon kept under moderate or strong temperature abuse conditions. After 15d at 8°C, cold-smoked salmon with added reuterin exhibited L.monocytogenes counts 2.0 log CFU/g lower than control smoked salmon with no reuterin added. At 30°C, reuterin also controlled the growth of the pathogen, with counts 1.4 and 0.9 log CFU/g lower than those observed in control smoked salmon after 24 and 48h, respectively. The addition of purified reuterin might be used as a hurdle technology to improve the safety and extend the shelf-life of lightly preserved seafood products such as cold-smoked salmon. © 2014 Elsevier Ltd.

Siles J.A.,CSIC - Experimental Station of El Zaidín | Pascual J.,Fundacion MEDINA | Gonzalez-Menendez V.,Fundacion MEDINA | Sampedro I.,CSIC - Experimental Station of El Zaidín | And 4 more authors.
Systematic and Applied Microbiology | Year: 2014

Dry olive residue (DOR) transformation by wood decomposing basidiomycetes (e.g. Coriolopsis floccosa) is a possible strategy for eliminating the liabilities related to the use of olive oil industry waste as an organic soil amendment. The effects of organic fertilization with DOR on the culturable soil microbiota are largely unknown. Therefore, the objectives of this study were to measure the short-term effects of DOR and C. floccosa-transformed DOR on the culturable bacterial soil community, while at the same time documenting the bacterial diversity of an agronomic soil in the southeastern Iberian Peninsula. The control soil was compared with the same soil treated with DOR and with C. floccosa-transformed DOR for 0, 30 and 60 days. Impact was measured from total viable cells and CFU counts, as well as the isolation and characterization of 900 strains by fatty acid methyl ester profiles and 16S rRNA partial sequencing. The bacterial diversity was distributed between Actinobacteria, Alphaproteobacteria, Gammaproteobacteria, Betaproteobacteria, Bacilli, Sphingobacteria and Cytophagia. Analysis of the treatments and controls demonstrated that soil amendment with untransformed DOR produced important changes in bacterial density and diversity. However, when C. floccosa-transformed DOR was applied, bacterial proliferation was observed but bacterial diversity was less affected, and the distribution of microorganisms was more similar to the unamended soil. © 2013 Elsevier GmbH.

Roemer T.,Merck Frosst Canada Ltd. | Xu D.,Merck Frosst Canada Ltd. | Xu D.,WuXi AppTec | Singh S.B.,Merck And Co. | And 5 more authors.
Chemistry and Biology | Year: 2011

Starting with the discovery of penicillin, the pharmaceutical industry has relied extensively on natural products (NPs) as an unparalleled source of bioactive small molecules suitable for antibiotic development. However, the discovery of structurally novel and chemically tractable NPs with suitable pharmacological properties as antibiotic leads has waned in recent decades. Today, the repetitive "rediscovery" of previously known NP classes with limited antibiotic lead potential dominates most industrial efforts. This limited productivity, exacerbated by the significant financial and resource requirements of such activities, has led to a broad de-emphasis of NP research by most pharmaceutical companies, including most recently Merck. Here we review our strategies - both technological and philosophical - in addressing current antifungal discovery bottlenecks in target identification and validation and how such efforts may improve NP-based antimicrobial discoveries when aligned with NP screening and dereplication. © 2011 Elsevier Ltd. All rights reserved.

Sanchez Marquez S.,CSIC - Institute of Natural Resources and Agriculture Biology of Salamanca | Bills G.F.,Fundacion MEDINA | Herrero N.,CSIC - Institute of Natural Resources and Agriculture Biology of Salamanca | Zabalgogeazcoa I.,CSIC - Institute of Natural Resources and Agriculture Biology of Salamanca
Fungal Ecology | Year: 2012

Many fungi behave as endophytes in grasses. Unlike the well known . Epichloë/. Neotyphodium species, most other endophytes are not capable of systemic colonization of plant organs, or seed transmission. The species diversity of the non-systemic endophytic mycobiota of grasses is large, dominated by ascomycetes. The relative abundance of species is very unequal, a few dominant taxa like . Acremonium, . Alternaria, . Cladosporium, . Epicoccum and . Penicillium spp., occur in many grasses and locations. In contrast, many rare species are isolated only once in endophyte surveys. The possible ecological functions of endophytes are diverse, and often unknown. Latent pathogens represent a small fraction of endophytic mycobiotas, indicating that many non-pathogenic fungal taxa are able to enter plants overriding defence reactions. Some dominant species behave as latent saprotrophs, sporulating when the host tissue dies. Endofungal viruses and bacteria occur among endophytic species, but their effect in their hosts is largely unknown. © 2011 Elsevier Ltd and The British Mycological Society.

Marquez S.S.,CSIC - Institute of Natural Resources and Agriculture Biology of Salamanca | Bills G.F.,Fundacion Medina | Acuna L.D.,CSIC - Institute of Natural Resources and Agriculture Biology of Salamanca | Zabalgogeazcoa I.,CSIC - Institute of Natural Resources and Agriculture Biology of Salamanca
Fungal Diversity | Year: 2010

Holcus lanatus is a grass that grows in humid, often waterlogged soils in temperate zones around the world. The purpose of this work was to identify fungal endophytes associated with its roots and leaves, and to describe the diversity and spatial distribution patterns found in its mycobiota. Holcus plants were sampled at 11 locations in western and northern Spain, and endophytes were isolated from leaves and roots of each plant. Morphological and molecular methods based on the ITS1-5.8SrRNA-ITS2 sequence were used for isolate identification. In total, 134 different species were identified, 77 occurred in leaves, 79 in roots, and 22 were common to both organs. The dominant species of the mycobiota were isolated from roots and leaves, and were species generally considered as multi-host endophytes. The species richness was similar in leaves and roots, but the composition of isolates from roots varied more among locations than in leaf mycobiotas, suggesting that soil characteristics may have strongly influenced the root mycobiota. Significant variations with respect to the composition of their mycobiota among different locations indicate that beta diversity is a first order factor governing the richness and distribution of the endophytic mycobiota in grasses. © Kevin D. Hyde 2010.

Sanchez Marquez S.,CSIC - Institute of Natural Resources and Agriculture Biology of Salamanca | Bills G.F.,Fundacion MEDINA | Zabalgogeazcoa I.,CSIC - Institute of Natural Resources and Agriculture Biology of Salamanca
Annals of Applied Biology | Year: 2011

In recent years, Mycosphaerella leaf disease (MLD) has become very common in Eucalyptus globulus plantations in Galicia, northwest Spain. The aetiology of MLD is complex and is associated with several species of Mycosphaerella and Teratosphaeria. A survey of the fungal mycobiota associated with juvenile and adult leaves and with leaf litter of the same trees in MLD-affected plantations was made. The goal was to identify pathogens and endophytes, to determine whether the mycobiota of each leaf type differed and whether leaf litter might be a reservoir of MLD inoculum. Fungi belonging to 113 different species were isolated from the leaves of juvenile and adult trees sampled at 10 locations; 81 species occurred in juvenile and 65 in adult leaves. The average number of species obtained from juvenile leaves was significantly greater (P > 0.01) compared to adult leaves. This difference suggested that juvenile leaves are not only more susceptible to a group of pathogens, but to a wide range of fungi. Therefore, a general resistance mechanism might be lacking or be less effective in juvenile than in adult leaves. Several pathogenic species were identified in both leaf types. Leaf litter and living leaf mycobiotas were very different. However, some of the species they shared were MLD pathogens, suggesting that leaf litter could contribute to the inoculum of MLD. © 2010 Association of Applied Biologists.

Genilloud O.,Fundacion MEDINA
Recent Patents on Anti-Infective Drug Discovery | Year: 2012

Microbial natural products have been for decades one of the most successful sources of drugs to treat infectious diseases. The high occurrence of resistances to all major classes of known antibiotics represents today a new challenge and new classes of antibacterial compounds are urgently needed to respond to this unmet clinical need. While natural products discovery programs have been gradually abandoned by big pharma, smaller biotechnology companies and other research organizations are taking the lead in the discovery of novel antibacterials. A survey of recent patents has shown that in spite of the efforts, few novel compounds are being developed that can overcome most of the emerging multi-resistant and pan-resistant pathogens. In order to respond to the current challenges of discovering novel antibiotics, new approaches are required to be developed to further exploit the microbial resources and their biosynthetic potential as an untapped source of novel metabolites. Strategies to mine microbial collections for orphan biosynthetic pathways and novel species thought to be uncultivable, are emerging as a need within antibacterial drug discovery programs, in combination with high throughput screening and chemical dereplication of novel compounds. Different innovative methods that are being developed to respond to the new challenges that are faced today by drug discovery programs will ensure the evolution of these strategies into a completely new framework that will address the renovated interest in the discovery of novel classes of antibiotics. © 2012 Bentham Science Publishers.

Genilloud O.,Fundacion MEDINA
Antonie van Leeuwenhoek, International Journal of General and Molecular Microbiology | Year: 2014

New classes of antibacterial compounds are urgently needed to respond to the high frequency of occurrence of resistances to all major classes of known antibiotics. Microbial natural products have been for decades one of the most successful sources of drugs to treat infectious diseases but today, the emerging unmet clinical need poses completely new challenges to the discovery of novel candidates with the desired properties to be developed as antibiotics. While natural products discovery programs have been gradually abandoned by the big pharma, smaller biotechnology companies and research organizations are taking over the lead in the discovery of novel antibacterials. Recent years have seen new approaches and technologies being developed and integrated in a multidisciplinary effort to further exploit microbial resources and their biosynthetic potential as an untapped source of novel molecules. New strategies to isolate novel species thought to be uncultivable, and synthetic biology approaches ranging from genome mining of microbial strains for cryptic biosynthetic pathways to their heterologous expression have been emerging in combination with high throughput sequencing platforms, integrated bioinformatic analysis, and on-site analytical detection and dereplication tools for novel compounds. These different innovative approaches are defining a completely new framework that is setting the bases for the future discovery of novel chemical scaffolds that should foster a renewed interest in the identification of novel classes of natural product antibiotics from the microbial world. © 2014 Springer International Publishing.

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