The fungal cell wall as a target for antifungal therapies
LSH 2003 1.2.5.5

INTRODUCTION

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Topics

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 are 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 those due to most important 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. This core consists of the component polysaccharides beta1-3 glucan and chitin, which are cross-linked to each other. The enzymes and reactions associated with the synthesis and the remodeling 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 this STREP is 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:

The fungal cell wall is required for fungal cell integrity and is essential for fungal growth and for virulence.
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 beta 1-3 glucan synthesis.

The STREP FungWall objectives are centered on the assembly of the cell wall polysaccharide skeleton. The enzymes and reactions associated with chitin, beta-glucan and mannan synthesis, beta-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 two main fungal pathogens in Europe, Candida albicans and Aspergillus fumigatus.

Consortium project

Members of this consortium have been selected on the basis of their track record, their experience in the analysis of the fungal cell wall and the complementarity in technologies, in fungal species studied and in research areas. The partnership includes also prominent non-european scientific experts in a scientific committee that will evaluate independently the scientific progresses in the project. The combined expertise of the partners guarantees a multidisciplinary approach that combines functional genomics and applied technologies.
To identify cell wall targets, 4 work packages have been defined:

WP1 studies chitin.
WP2 will revisit beta-1-3 glucan synthesis.
Branching and cross-linking between chitin and beta-1-3 glucan will form the WP3.
WP4 will study O-mannosylation.

Expertise

A broad range of facilities and technological expertise are available within the consortium. These include:

• Transcriptomics and DNA array facilities (partners 1, 2, 3, 4, 7, 8)
• Proteomics and mass spectrometric facilities (partners 2, 3, 4, 8)
• Bioinformatics (partners 5, 9)
• Mutant library construction (partners 3, 6, 7, 8, 10)
• Polysaccharidomics (partner 1)
• Crystallography and X-Ray analysis (partners 5, 9)
• Heterologous protein production (partners 4, 7, 10)
• Protein-polysaccharide interactions (partners 1, 3, 4, 9)
• Gene regulation (partners 2, 4, 6, 7, 8)
• Bioproduction (partner 1)
• Animal facilities (partners 1, 2)
• Cell (macrophages, neutrophil) culture facilities (partners 1, 2)

The three fungal species covered by the consortium are the human pathogens C. albicans (partners 2, 3, 8, 9, 10), A. fumigatus (partners 1, 6, 9, 10), and the model yeast S. cerevisiae (partners 2, 3, 4, 6, 7, 8, 10).

Your questions

Any question about this project? Scientific topics and person to contact:

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