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News Article | April 28, 2017
Site: www.eurekalert.org

An international team of researchers have discovered a remarkable microbe with a Jekyll and Hyde character. The bacterium Burkholderia gladioli lives in specific organs of a plant-feeding beetle and defends the insect's eggs from detrimental fungi by producing antibiotics. However, when transferred to a plant, the bacterium can spread throughout the tissues and negatively affect the plant. Microbes are not always hostile players when interacting with animals and plants, they can also be powerful allies. In fact, transitions between antagonistic and cooperative lifestyles in microbes are likely not an exception, although such shifts have rarely been observed directly. In a new study published in Nature Communications, researchers from Johannes Gutenberg University Mainz (JGU), the Max Planck Institute for Chemical Ecology and the Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute (HKI) - in Jena, and the Universidad Estadual Paulista in Rio Claro, Brazil, gathered evidence for such a transition. Like many other insects, a group of herbivorous beetles, the Lagriinae, is in great need of an efficient defense. They lay their eggs on humid soil under leaf litter, where encounters with mold fungi are guaranteed. Researchers lead by Professor Martin Kaltenpoth from Mainz University have now discovered that the presence of a special bacterium, Burkholderia gladioli, on the eggs of the beetle Lagria villosa strongly reduces the risk of fungal infection and helps them survive. "Even when we applied mold fungi to the beetle's eggs, those with their symbiotic microbe present remained clean, whereas those without were often overgrown by a lawn of fungi", said first author Dr. Laura Flórez, who performed the experiments for her PhD project at the Max Planck Institute for Chemical Ecology in Jena, describing one of the key findings. Although some other insects also rely on microbes for protection against natural enemies, a microbial defense of the vulnerable egg stage was unknown. How is the protection of the nutrient-rich beetle eggs achieved? Chemical analyses revealed four different antibiotics produced by the beetle's microbial bodyguards. While two of these were already known, the other two molecules had not been described before. "We were particularly surprised to find a new chemical that looks much more like a plant defense compound than a bacterial antibiotic", said Professor Christian Hertweck from the Leibniz Institute for Natural Product Research and Infection Biology, who guided the chemical analyses. All four compounds inhibited the growth of other microbes; some were active against fungi, others against bacteria. This chemical armory likely shields the beetle's eggs from a broad spectrum of detrimental microbes. Surprisingly, the beetle's allies are very closely related to plant pathogens. And indeed, when the scientists applied the bacteria to soybean plants, a common food source of L. villosa beetles in nature, the microbes spread throughout the plants. There they had a negative impact as the infection resulted in the production of fewer beans as compared to control plants. But do the bacteria actually have a chance to leave the beetle and infect the plant in nature? An additional experiment demonstrated that they do. After beetles were confined to soybean leaves for three days, the bacteria genetic material could be detected in the leaves. That this is likely relevant in nature is shown by an analysis of five related beetle species: all contained Burkholderia gladioli strains, but these were more closely related to other environmental or plant-associated Burkholderia gladioli strains than to each other. Thus, the bacteria likely hitch a ride on the beetles to jump from plant to plant. There are many described cases of insects that carry microorganisms between plants. "What is interesting in the Lagria beetles is that their bacterial hitchhikers have turned into chemically-armed bodyguards", explained Professor Martin Kaltenpoth. In addition, the ability of this bacterium to produce previously unknown bioactive compounds highlights partnerships between insects and microbes as promising sources of novel antibiotics that may help to fight increasingly resistant human pathogens.

Hertweck C.,Leibniz Institute for Natural Product Research and Infection Biology | Hertweck C.,Friedrich - Schiller University of Jena
Trends in Biochemical Sciences | Year: 2015

Bacterial modular type I polyketide synthases (PKSs) represent giant megasynthases that produce a vast number of complex polyketides, many of which are pharmaceutically relevant. This review highlights recent advances in elucidating the mechanism of bacterial type I PKSs and associated enzymes, and outlines the ramifications of this knowledge for synthetic biology approaches to expand structural diversity. New insights into biosynthetic codes and structures of thiotemplate systems pave the way to rational bioengineering strategies. Through advances in genome mining, DNA recombination technologies, and biochemical analyses, the toolbox of non-canonical polyketide-modifying enzymes has been greatly enlarged. In addition to various chain-branching and chain-fusing enzymes, an increasing set of scaffold modifying biocatalysts is now available for synthetically hard-to-emulate reactions. © 2015 Elsevier Ltd.

Luo S.,Leibniz Institute for Natural Product Research and Infection Biology
The Journal of infectious diseases | Year: 2013

Candida albicans uses human complement regulators such as factor H and factor H-like protein 1 (FHL-1) for immune evasion. To define the whole panel of fungal complement-evasion molecules, C. albicans cell extract was absorbed to a factor H-coupled matrix. One 52-kDa protein was eluted and identified by mass spectrometry as glycerol-3-phosphate dehydrogenase 2 (Gpd2). Consequently, Gpd2 was recombinantly expressed and purified. Recombinant Gpd2 binds factor Hand and FHL-1, mainly via short consensus repeat 7; and binds plasminogen, via lysine residues. The 3 human complement regulators, when attached to candida Gpd2, became functionally active, and the attached host proteins assist in inactivation of the complement cascade or cleave fibrinogen in the extracellular matrix component fibrinogen. Polyclonal Gpd2 antiserum was generated and localized Gpd2 at the surface of C. albicans. In addition, candida Gpd2 bound to human nonphagocytic cells but not to phagocytic U937 cells. Thus, candida Gpd2 is a novel fungal immune evasion protein that binds several human complement regulators and, in addition, binds human cells.

Kniemeyer O.,Leibniz Institute for Natural Product Research and Infection Biology
Proteomics | Year: 2011

Fungal species of the genus Aspergillus play significant roles as model organisms in basic research, as "cell factories" for the production of organic acids, pharmaceuticals or industrially important enzymes and as pathogens causing superficial and invasive infections in animals and humans. The release of the genome sequences of several Aspergillus sp. has paved the way for global analyses of protein expression in Aspergilli including the characterisation of proteins, which have not designated any function. With the application of proteomic methods, particularly 2-D gel and LC-MS/MS-based methods, first insights into the composition of the proteome of Aspergilli under different growth and stress conditions could be gained. Putative targets of global regulators led to the improvement of industrially relevant Aspergillus strains and so far not described Aspergillus antigens have already been discovered. Here, I review the recent proteome data generated for the species Aspergillus nidulans, Aspergillus fumigatus, Aspergillus niger, Aspergillus terreus, Aspergillus flavus and Aspergillus oryzae. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Scherlach K.,Leibniz Institute for Natural Product Research and Infection Biology | Graupner K.,Leibniz Institute for Natural Product Research and Infection Biology | Hertweck C.,Leibniz Institute for Natural Product Research and Infection Biology
Annual Review of Microbiology | Year: 2013

This review focuses on bacteria-fungi interactions mediated by secondary metabolites that occur in the environment and have implications for medicine and biotechnology. Bipartite interactions that affect agriculture as well as relationships involving additional partners (plants and animals) are discussed. The advantages of microbial interplay for food production and the risks regarding food safety are presented. Furthermore, recent developments in decoding the impact of bacteria-fungi interactions on infection processes and their implications for human health are highlighted. In addition, this reviews aims to demonstrate how the understanding of complex microbial interactions found in nature can be exploited for the discovery of new therapeutics. © Copyright ©2013 by Annual Reviews. All rights reserved.

Hertweck C.,Leibniz Institute for Natural Product Research and Infection Biology | Hertweck C.,Friedrich - Schiller University of Jena
Angewandte Chemie - International Edition | Year: 2015

An end to suffering: Parasitic infections with protozoa and worms cause unimaginable misery, in particular in the tropics. Fortunately, natural products, such as the antimalarial artemisinin (1) and the anthelmintic avermectin (2) were discovered and developed into therapeutics. These major achievements now culminated in the 2015 Nobel Prize for Medicine. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hertweck C.,Leibniz Institute for Natural Product Research and Infection Biology
Journal of the American Chemical Society | Year: 2010

Genetic manipulation of the LuxR-type quorum sensing regulator system in Burkholderia thailandensis caused a significant change in the metabolic profile: it led to activation of the thailandamide biosynthesis gene cluster, dramatically increased thailandamide production, and induced strong pigmentation. A novel polyketide metabolite, thailandamide lactone (2), which cannot be detected in the wild type, was isolated from the mutant broth, and its structure was elucidated by high-resolution mass spectrometry and IR and NMR spectroscopy. In a biological assay using tumor cell lines, 2 showed moderate antiproliferative activities. This finding not only points to complex regulation but also serves as a proof of concept that engineering quorum sensing mutants may enable the discovery of novel bioactive natural products encoded by silent or only weakly expressed biosynthetic pathway genes. © 2010 American Chemical Society.

Priebe S.,Leibniz Institute for Natural Product Research and Infection Biology
PloS one | Year: 2013

Glucose restriction mimicked by feeding the roundworm Caenorhabditis elegans with 2-deoxy-D-glucose (DOG) - a glucose molecule that lacks the ability to undergo glycolysis - has been found to increase the life span of the nematodes considerably. To facilitate understanding of the molecular mechanisms behind this life extension, we analyzed transcriptomes of DOG-treated and untreated roundworms obtained by RNA-seq at different ages. We found that, depending on age, DOG changes the magnitude of the expression values of about 2 to 24 percent of the genes significantly, although our results reveal that the gross changes introduced by DOG are small compared to the age-induced changes. We found that 27 genes are constantly either up- or down-regulated by DOG over the whole life span, among them several members of the cytochrome P450 family. The monotonic change with age of the temporal expression patterns of the genes was investigated, leading to the result that 21 genes reverse their monotonic behaviour under impaired glycolysis. Put simply, the DOG-treatment reduces the gross transcriptional activity but increases the interconnectedness of gene expression. However, a detailed analysis of network parameters discloses that the introduced changes differ remarkably between individual signalling pathways. We found a reorganization of the hubs of the mTOR pathway when standard diet is replaced by DOG feeding. By constructing correlation based difference networks, we identified those signalling pathways that are most vigorously changed by impaired glycolysis. Taken together, we have found a number of genes and pathways that are potentially involved in the DOG-driven extension of life span of C. elegans. Furthermore, our results demonstrate how the network structure of ageing-relevant signalling pathways is reorganised under impaired glycolysis.

Leibniz Institute for Natural Product Research and Infection Biology | Date: 2010-12-22

The present invention relates to novel benzothiazinone derivatives and their use as antibacterial agents in infectious diseases of mammals (humans and animals) caused by bacteria, especially diseases like tuberculosis (TB) and leprosy caused by mycobacteria. The present invention aims at the generation of new compounds with activity against mycobacteria as potential new tuberculosis drugs to overcome problems concerning resistance and drug intolerance. The solution of the present invention is a compound of formula I wherein R^(1 )to R^(6 )are as defined in the specification.

Miltenyi Biotec GmbH, Leibniz Institute for Natural Product Research and Infection Biology | Date: 2015-08-12

The present invention provides the in-vitro use of at least one in-vivo-target antigen of Aspergillus fumigatus for selective activation, detection and/or analysis of Aspergillus fumigatus specific CD4^(+) T cells in a sample comprising cells, wherein said at least one in-vivo-target antigen reveals an immune reactivity characterized by i) the in vivo existence of antigen-specific T cells comprising more than 60% memory T cells and ii) said antigen-specific T cells further comprise T cells able to produce IFN-gamma upon stimulation at a frequency between 15% and 80% and/or IL17 upon stimulation at a frequency between 5% and 30%. Said at least one in-vivo-target antigen may be selected from the group consisting of antigens Scw4, Pst1, Shm2, GliT and TpiA or fragments thereof. Also provided are a method, a composition, and a kit thereof.

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