Fungal pathogens represent the major eukaryotic agents of serious infection in European countries. Infections due to Candida albicans and Aspergillus fumigatus are the most common and clinically important pathogens and were therefore the focus of this project. The repertoire of available antifungal chemotherapeutic agents is inadequate to treat life-threatening infections that are characterised by morbidities that exceed in Europe those due to most important parasitic, bacterial and viral diseases. Therefore there is an urgent need to generate new, efficacious, non-toxic compounds with broad-spectrum antifungal activity. The fungal wall is the skeleton and armour of the fungus but potentially also its Achilles heel since the major components are absent from mammals and can be specifically targeted with compounds that do not affect human metabolism. We have focused our programme on the core cell wall structure that is common to all fungal pathogens and is essential for their growth and viability. The enzymes and reactions associated with the synthesis and the remodelling of these major cell wall polysaccharides as well as the sensing mechanisms important in cell wall integrity and remoulding during morphogenetic processes will be investigated. The challenge for FUNGWALL was to investigate mechanisms of fungal cell wall synthesis in order to identify new antifungal targets to control human fungal infections in Europe.
The cell wall of pathogenic fungi is a good target for the development of new drugs for the following reasons: (1) The fungal cell wall is required for fungal cell integrity and is essential for fungal growth and for virulence; (2) Polysaccharidic components of the cell wall are unique to fungi and consequently, putative inhibitors of the biosynthetic pathways responsible for cell wall construction can be potent antifungals, as shown by the recent launch by big Pharmas of drugs inhibiting 1-3 glucan synthesis.
The objectives of FUNGWALL are centered on the assembly of the cell wall polysaccharide skeleton. The enzymes and reactions associated with chitin, glucan and mannan synthesis, glucan cross-linking and branching will be investigated. New post genomic approaches will enable us to first revisit old targets, define novel targets and to screen for novel compounds that disrupt the integrity of the cell wall with the goal of identifying new generation antifungals that target fungal cell wall biosynthesis. These studies will use primarily the 2 main fungal pathogens in Europe, Candida albicans and Aspergillus fumigatus.
To identify cell wall targets, 4 work packages were defined:
Bringing together the leading laboratories in Europe working on cell wall analysis in fungi, the 36-month FUNGWALL project led to the following achievements:
As regards the state-of-the-art, the achievements of the project have placed Europe in a leading position in the world for the analysis of fungal cell wall. The coupling of biochemical and genetic methodologies was extremely synergetic to tackle this problem and have given a unique flavour to FUNGWALL. A close contract between the different members of the STREP will now continue and will lead to new scientific developments in the area.
In terms of impact of the project on its industry or research sector, major achievements have resulted from the new multidisciplinary genomic and post genomic approaches undertaken. Among them:
Finally, several new drug targets were identified during the course of FUNGWALL:
Most strains have been engineered which could be very useful tools in the search for new drugs.
For example, chitin synthase mutants are now available for looking for specific antifungal drugs in both Candida and Aspergillus. Although new drug targets were identified and old ones successfully revisited, we have assisted during the course of this STREP to a reduction in the research and developments efforts put by the pharmaceutical industry in the antifungal business. The chances to see new drugs developed by these companies in the near future are very limited. To palliate this, we have also embarked in a combination therapy strategy that has been based on the research of this STREP on fungal cell wall biosynthesis. It will lead to promising results in the management of patients in Europe suffering from systematic fungal infections. This may lead to new formulation of existing antifungal drugs, a very promising development for SMES.