Eccles, United Kingdom
Eccles, United Kingdom

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Grant
Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: PEOPLE-2007-1-1-ITN | Award Amount: 3.64M | Year: 2008

The vision of the FINSysB Network is to generate bright, ambitious and well-trained young researchers capable of contributing significantly to the knowledge-base and economy of the European Union. We will achieve this goal by providing a strong, multidisciplinary training for early stage and experienced researchers in the pathobiology, genomics, molecular biology, bioinformatics and systems biology of the medically important fungus, Candida albicans. This microbe causes frequent infections in otherwise healthy individuals and is a common cause of potentially lethal hospital acquired infections in intensive care patients in the EU. Our well-integrated research programme will dissect and model the molecular interactions that take place between this fungal pathogen and its human host during disease progression. FINSysB partners are all internationally renowned, contributing complementary expertise in pathobiology, genomics, molecular biology, bioinformatics and systems biology. Our two SME partners provide a well-defined route for the translation of our research into the development of novel, clinically useful diagnostic tools and antifungal therapies. Our research activities will be supplemented by well-structured training programmes in research skills and complementary transferable skills. This training extends successful programmes that were established during FP6. They will impart state-of-the-art skills in modern predictive and experimental biology as well as useful generic skills. The personal development plans of our young researchers will be enhanced further by secondments to industrial and academic partners and by attendance at advanced summer schools (e.g. on Human Fungal Pathogens, and Yeast Systems Biology). Using this combination of approaches we will provide our early stage and experienced researchers with well-defined career opportunities and equip them with the tools to compete effectively on the international stage.


Grant
Agency: Cordis | Branch: FP7 | Program: MC-ITN | Phase: FP7-PEOPLE-2013-ITN | Award Amount: 3.91M | Year: 2013

Cell polarity and directed growth (tropism) are fundamental biological processes. Most fungi are dependent on these processes because they grow as polarised filaments called hyphae, whose growth and developmentare governed by physical and chemical cues from the environment. Such cues include surface-contact, light, nutrients, mating partners, host organisms, or self hyphae from within the fungal colony. The capacity to re-orient hyphal tip growth in response to external signals forms the basis of the saprotropic, symbiotic and parasitic lifestyles of fungi. For example, dimorphic transitions and directed hyphal growth are intimately associated with virulence in fungal pathogens. The cellular components that control these morphogenic decisions therefore play key roles in fungal adaptation to environmental change and the invasion stages of infectious growth. Extensive background work has led to the emerging concept of a fungal brain, which integrates exogenous and endogenous signals to determine the shape and direction of hyphae, both at the levels of the individual cell and of the fungal colony. However, in spite of the universal importance of these processes, surprisingly little is known about their genetic and cellular bases. FUNGIBRAIN brings together pioneering expertise from fungal model organisms such as bakers yeast, fission yeast and the filamentous yeast Ashbya gossypii, and world-class teams working on filamentous fungi, including important human or plant pathogens (Aspergillus fumigatus, Candida albicans, Fusarium oxysporum and Ustilago maydis). The project integrates genetic, biochemical, biophysical, cell biology and systems biology approaches to define common patterns of signal integration and hyphal tropism. Early evidence suggests that these cellular targets are conserved across a broad range of fungal species and thus will have direct and important applications in antifungal treatments and biotechnology.


PubMed | University of Texas Health Science Center at San Antonio, University of Liverpool, Cresset and F2G Ltd.
Type: | Journal: Proceedings of the National Academy of Sciences of the United States of America | Year: 2016

There is an important medical need for new antifungal agents with novel mechanisms of action to treat the increasing number of patients with life-threatening systemic fungal disease and to overcome the growing problem of resistance to current therapies. F901318, the leading representative of a novel class of drug, the orotomides, is an antifungal drug in clinical development that demonstrates excellent potency against a broad range of dimorphic and filamentous fungi. In vitro susceptibility testing of F901318 against more than 100 strains from the four main pathogenic Aspergillus spp. revealed minimal inhibitory concentrations of 0.06 g/mL-greater potency than the leading antifungal classes. An investigation into the mechanism of action of F901318 found that it acts via inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) in a fungal-specific manner. Homology modeling of Aspergillus fumigatus DHODH has identified a predicted binding mode of the inhibitor and important interacting amino acid residues. In a murine pulmonary model of aspergillosis, F901318 displays in vivo efficacy against a strain of A. fumigatus sensitive to the azole class of antifungals and a strain displaying an azole-resistant phenotype. F901318 is currently in late Phase 1 clinical trials, offering hope that the antifungal armamentarium can be expanded to include a class of agent with a mechanism of action distinct from currently marketed antifungals.


Bowyer P.,University of Manchester | Mosquera J.,University of Manchester | Anderson M.,University of Manchester | Birch M.,F2G Ltd. | And 2 more authors.
FEMS Microbiology Letters | Year: 2012

Azoles are currently the mainstay of antifungal treatment both in agricultural and in clinical settings. Although the target site of azole action is well studied, the basis of azole resistance and the ultimate mode of action of the drug in fungi are poorly understood. To gain a deeper insight into these aspects of azole action, restriction-mediated plasmid integration (REMI) was used to create azole sensitive and resistant strains of the clinically important fungus Aspergillus fumigatus. Four azole sensitive insertions and four azole-resistant insertions were characterized. Three phenotypes could be re-created in wild-type AF210 by reintegration of rescued plasmid and a further four could be confirmed by complementation of the mutant phenotype with a copy of the wild-type gene predicted to be disrupted by the original insertional event. Six insertions were in genes not previously associated with azole sensitivity or resistance. Two insertions occur in transporter genes that may affect drug efflux, whereas others may affect transcriptional regulation of sterol biosynthesis genes and NADH metabolism in the mitochondrion. Two insertions are in genes of unknown function. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.


Oliver J.D.,F2G Ltd | Kaye S.J.,F2G Ltd | Tuckwell D.,F2G Ltd | Johns A.E.,University of Manchester | And 5 more authors.
PLoS ONE | Year: 2012

Dihydroxyacid dehydratase (DHAD) is a key enzyme in the branched-chain amino acid biosynthetic pathway that exists in a variety of organisms, including fungi, plants and bacteria, but not humans. In this study we identified four putative DHAD genes from the filamentous fungus Aspergillus fumigatus by homology to Saccharomyces cerevisiae ILV3. Two of these genes, AFUA_2G14210 and AFUA_1G03550, initially designated AfIlv3A and AfIlv3B for this study, clustered in the same group as S. cerevisiae ILV3 following phylogenetic analysis. To investigate the functions of these genes, AfIlv3A and AfIlv3B were knocked out in A. fumigatus. Deletion of AfIlv3B gave no apparent phenotype whereas the Δilv3A strain required supplementation with isoleucine and valine for growth. Thus, AfIlv3A is required for branched-chain amino acid synthesis in A. fumigatus. A recombinant AfIlv3A protein derived from AFUA_2G14210 was shown to have DHAD activity in an in vitro assay, confirming that AfIlv3A is a DHAD. In addition we show that mutants lacking AfIlv3A and ilv3B exhibit reduced levels of virulence in murine infection models, emphasising the importance of branched-chain amino acid biosynthesis in fungal infections, and hence the potential of targeting this pathway with antifungal agents. Here we propose that AfIlv3A/AFUA_2G2410 be named ilvC. © 2012 Oliver et al.


Grant
Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2013.2.3.1-1 | Award Amount: 6.11M | Year: 2013

Invasive fungal diseases are estimated to kill 1.5 million people each year. The incidence of mortality has risen significantly across the EU over the last 20 years due to an expansion of at risk patient populations. Given the obvious importance of these diseases it is perhaps surprising that only four classes of drug are available to treat systemic fungal infection. The azole class of antifungals provide the front line role for most disease treatment but recently resistance has emerged and it is of growing concern that levels are rising dramatically. European researchers have led the world in identifying the extent of the problem with some centres reporting itraconazole resistance in the Aspergillus species as high as 20% and in Candida, resistance to posaconazole upto 30%. Additionally the epidemiology of serious fungal infections is changing with more intrinsically resistant organisms now being seen more frequently. This represents a major problem for clinicians who are increasingly treating infections for which there is no current effective therapy. This proposal brings together leading European SMEs and academics to address this problem through the development of novel classes of antifungals and the identification of novel drug targets. The NOFUN consortium has identified potent novel broad spectrum antifungal molecules that are active against multi-resistant fungal pathogens and intends to qualify these as drug candidates. One of these assets is already at the lead identification stage. Cutting edge fungal genomics will be used to identify novel druggable targets and advance these to develop qualified tractable chemical inhibitors. With its wide ranging expertise across medicinal chemistry, ADMET, fungal biology, chemical genomics and drug development the partners will build and progress a broad pipeline of agents that have the potential to reach the clinic within 5 years.


Allen G.,University of Sheffield | Bromley M.,F2G Ltd. | Kaye S.J.,F2G Ltd. | Keszenman-Pereyra D.,University of Sheffield | And 5 more authors.
Fungal Genetics and Biology | Year: 2011

The mitochondrial phosphopantetheinyl transferase gene pptB of the opportunistic pathogen Aspergillus fumigatus has been identified and characterised. Unlike pptA, which is required for lysine biosynthesis, secondary metabolism, and iron assimilation, pptB is essential for viability. PptB is located in the mitochondria. In vitro expression of pptA and pptB has shown that PptB is specific for the mitochondrial acyl carrier protein AcpA. © 2010 Elsevier Inc.


Grant
Agency: GTR | Branch: Innovate UK | Program: | Phase: Feasibility Study | Award Amount: 1.33M | Year: 2014

Systemic fungal disease is a life threatening groups of infections caused by yeasts and moulds that affects people who have impaired immune systems. The numbers of patients are increasing and the current threatment options are limited to three types of antifungal drug. Often these drugs have severe side effects or cant be used with other medicines. F2G has identified a new type of antifungal that works through a different mechanism. It is highly potent against many of the moulds that cause these serious infections. This project aims to develop this new antifungal drug by testing its safety in man and how it interacts with other drugs. Following this project the drug can be tested in patients suffering from serious infection.

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