Grant: Operating Grant

Fungal infections are very difficult to treat. There are relatively few good antifungal drugs and many fungal pathogens possess resistance mechanisms that render these few drugs relatively useless. One source of new drugs is the 'secondary metabolism' of the streptomycetes bacteria. More than 70% of the existing antibacterial drugs come from this source as well as a much smaller number of antifungals. Our research demonstrates that there are many more antifungals to be discovered from this source than has ever been appreciated before. However the compounds are difficult to purify and study because they are not produced during laboratory culture. To address this problem we have developed a chemical trigger that can be added to growth medium to activatethe genes for these secondary metabolic pathways. We have demonstrated that we can identify and purify potent antifungals using this approach and that many of them are novel molecules. Our aim in this proposal is to purify a collection of 45 candidate activities that we have discovered, solve their structures and understand how they work. This will involve both the investigation of their molecular mechanism of action and their possible efficacy as antifungal drugs using animal models of infection. Our aim is to have a transformative effect on the discovery of new drugs in academia and the pharmaceutical sector.