Chemical and genetic 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 chemotherapy, organ transplants or HIV infection, these microbes are able to establish lethal infections that are not 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 protective cell wall that surrounds 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 fungal pathogen Aspergillus fumigatus is one of the leading causes of invasive fungal disease. The incidence of invasive aspergillosis has remained high due to a combination of a rising population of immunocompromised patients and the emergence of resistance against a small arsenal of only partially effective antifungal drugs. There is thus an urgent need for novel, properly genetically and chemically validated, drug targets. The Aspergillus cell wall consists of chitin, glucan and mannan. Despite an emerging understanding of the complex membrane proteins involved in the synthesis of these polymers, targeting them has proven difficult. Instead, in this proposal we aim to target "Achilles heels" of cell wall synthesis - the production of the sugar nucleotide precursors UDP-Glc, UDP-GlcNAc, GDP-Man and regulators of glucan synthase, that will cut deep into the essential cell wall biosynthetic machinery. Building on a significant body of unpublished preliminary data, this proposal uses a multidisciplinary approach (covering genetics, biochemistry, structural biology, fragment-based inhibitor discovery,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 from these pathways as antifungal targets. The output will be:

1) a significant increase in our molecular understanding of these biosynthetic enzymes,

2) novel chemical tools to probe these pathways and their interactions with known antifungals, and

3) a portfolio of targets (and associated strains, protein structures and chemical starting points) that can serve as a springboard for future antifungal drug discovery by follow-up academic translational research and/or the pharmaceutical industry beyond the end of this MRC Programme Grant.

Intellectual property and engagement with the commercial sector
Aspergillus fumigatus is one of the three most common causes of fungal infections and is 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 School of Life Sciences has a great deal of experience in engaging with industry regarding commercialisation of discoveries. RIS have an office within the SLS 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 readily. 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. The University of Dundee has a formal collaboration with Dundee Science Centre, Abertay University, and the 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 and has already run in 2016 and 2018 in association with professional educators at the Dundee Science Centre. The PI will participate in future re-runs of both of these events, and the PDs associated with this project will receive training to allow them to participate. I anticipate presenting aspects of the proposed project at least once during this time.