Wednesday, 29 September 2010

New Research to Help Identify Targets for New Antifungals

One of the first requirements to begin development of a new antifungal drug is to identify what target the drug will be aimed at. The target must be specific and not exist in human cells so that the drug does not affect the patient, and it must be effective in that it must attack part of the fungus that is vital for its growth.
Currently we have a series of antifungal drugs that fall into three broad categories,
  • those that target the cell wall (something that does not exist in mammals) that the fungus relies on for physical cell integrity e.g. echinocandins: caspofungin, micafungin, and anidulafungin. These tend to be very safe and have fewer side effects.
  • those that target the cell membrane e.g. amphotericin B, azoles (Itraconazole, voriconazole, posaconazole etc). Mammalian (including human)  cells have a cell membrane so this is a less specific target. These drugs target chemicals (ergosterols) that are far more plentiful in fungal cell membranes than they are in mammalian cell membranes so fungi are hit a lot harder than mammalian cells by these drugs. Consequently these drugs are effective at tackling fungal infections but do become toxic to humans if the dose is too high - a lot of care is taken with the use of these drugs to ensure dose is optimised and side effects are minimised. 
  • those that target DNA/RNA synthesis e.g. flucytosine. Mammalian cells make extensive use of DNA & RNA so this drug lacks specificity. Difficult to use.
Clearly the best existing target in terms of specificity is the cell wall. In this news report it states that this research group have just announced the $1.5 million funding of new research into drugs that will act on a component of the construction of cell walls (UDP-galactopyranose mutase) in fungi with the aim of disrupting the process and thus making it very difficult for the fungus to make its own cell wall and grow normally. This particular target has not been utilised for antifungal drugs before now and we already know that if the gene for UDP-galactopyranose mutase is knocked out by genetic manupulation the ability of Aspergillus fumigatus to infect mammals is significantly impaired (reduced virulence) so it is likely that inhibiting its activity using a new drug will inhibit infection.

Galactofuranose (the chemical made by UDP-galactopyranose mutase) is extensively used by A. fumigatus and is already being  investigated as a molecule we could use to detect infection by this fungal pathogen, so further research into this molecule has the potential to improve diagnosis, detection and treatment of A. fumigatus infections.

The prospects for this antifungal target look good though of course there are many hurdles to overcome yet, but this is certainly one of the possibilities for improving the treatment of fungal infections, possibly serious fungal infections caused by Aspergillus fumigatus.

Characterization of recombinant UDP-galactopyranose mutase from Aspergillus fumigatus
Targeted Gene Deletion of
Leishmania major UDP-galactopyranose Mutase Leads to Attenuated Virulence

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