Genetic, structural and chemical validation of Aspergillus fumigatus cell wall targets

"Fungi" are types of bugs that are widespread and most of us carry some of these organisms. Normally our immune system is perfectly capable of suppressing their growth. However, under conditions where the immune system is weakened, for instance during chemotheraphy, organ transplants or HIV infection, these microbes are able to establish lethal infections that are not uniformly/well treatable with currently available drugs - there is a significant unmet medical need. This proposal aims to give us an understanding of proteins that are important for building the "cell wall" of the fungal pathogen A. fumigatus - a structure that protects this microbe from its environment. This work will ultimately lead to the identification of opportunities for the discovery of novel anti-fungal drugs by the pharmaceutical industry.

The cell wall of the opportunistic fungal pathogen Aspergillus fumigatus is a dynamic and multi-layered structure consisting of the sugar polymers chitin, glucan and (galacto)mannan. Despite decades of work, there are huge gaps in our knowledge of the enzymes responsible for cell wall biogenesis. This is particularly pressing given the significant rise of fatal A. fumigatus infections in immunocompromised patients, and thus the need for novel, properly genetically and chemically validated, drug targets. This proposal uses a multidisciplinary approach (covering genetics, biochemistry, structural biology, fragment-based inhibitor discovery, synthetic chemistry and cell biology) to genetically, structurally and chemically validate A. fumigatus enzymes involved in fungal cell wall biogenesis as targets. The proposal covers three areas:

UDP-GlcNAc biosynthesis - exploiting a significant body of preliminary data to use fragment-based approaches to generate tools for chemical validation of this pathway.

Cell wall synthesis - with the aims of generating overexpression systems and crystal structures for enzymes involved in chitin/glucan synthesis and developing novel assays to discover inhibitors that will aid in chemical validation of these targets.

Cell wall modification - with the aims of genetically and chemically validating chitinases, chitin deacetylases and glucan transglycosylases.

The output will be:
1) A significant increase in our molecular understanding of fungal cell wall biogenesis enzymes,
2) A collection of novel chemical tools for use by the fungal scientific community, and
3) A portfolio of targets (and associated strains, protein structures and chemical starting points) that can serve as a springboard for novel antifungal drug discovery by follow-up translational research and/or the pharmaceutical industry.

Intellectual property and engagement with the commercial sector
Aspergillus fumigatus is one of the three most common causes of fungal infections and associated with a number of life-threatening diseases. The increasing frequency of azole resistant A. fumigatus infections over the last decade is anticipated to become a growing health concern. This project seeks fundamental understanding, at the molecular level, of A. fumigatus cell wall biogenesis which is an essential structure unique to fungi. This scientific underpinning may ultimately inform the development of new therapeutic agents. Commercial exploitation will be through patenting of intellectual property, spin-out, and licensing via the University of Dundee Research and Innovation Services (RIS). The College of Life Science has a great deal of experience of engaging with industry regarding commercialisation of discoveries. RIS have an office within the CLS research complex and the team have a large number of industrial contacts and close links to Scottish Enterprise. This will help to maximise the impact of all findings of commercial value.

The PI is a founding member of the Drug Discovery Unit (DDU) at the University of Dundee. The DDU was established in 2006 in the College of Life Sciences, with the aim of translating basic science into lead compounds to validate putative drug targets, to provide tools to investigate disease pathways and, when appropriate, generate pre-clinical drug candidates. The DDU has a Proof-of-Concept group able to pioneer early stages of drug discovery - ligand binding assay development, screening, and limited medicinal chemistry input. Their engagement, working on the chemical entities and validated targets produced by this project, would help us move this project towards a large strategic translational award in 5 years time. We will work closely with RIS to identify pharmaceutical companies with whom we can engage in the process of antifungal drug development. We would seek either a licencing agreement or direct support.

Communications and Public Engagement
The primary mechanism for communication of this research will be through publication in peer review international journals. Open access publishing options will be used to ensure that the results are available rapidly. We will liaise at the time of publication with the University of Dundee, and MRC Press offices to ensure publicity of results of interest to the general public. Communication with potential Industrial beneficiaries will take place via the Research and Innovations Service at the University of Dundee.

The College of Life Sciences at the University of Dundee is proactive in engaging the public. The College has an Associate Dean with responsibility for public engagement and we have a public engagement web page that is specifically aimed at the non-specialist and allows interaction by the public after events. "Sensation: Dundee Science Centre" is the local science centre - the University of Dundee has a formal collaboration with the Dundee Science Centre, Abertay University, and Scottish Enterprise for a program called "Revealing Research". Revealing Research engages and informs members of the public about the scientific research being performed in their home city. Since 2009, the PI has been involved in public engagement activities. He helped to develop a signature outreach event run by the Division of Molecular Microbiology, termed "Magnificent Microbes". This event is biannual - it has already run in 2010 and 2012, in association with professional educators at the Dundee Science Centre. The PI will participate in both of these events, and the PDs associated with this project will also receive training to allow them to participate. I anticipate presenting some of the aspects of the proposed project at least once during this time.