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Systematic Chemical Genetic Interrogation of Biological Networks

Final Report Summary - SCG (Systematic Chemical Genetic Interrogation of Biological Networks)

The characteristics of every species and every individual within a species derive from the highly interconnected network of genes encoded in the genome. The overall aim of our ERC project was to exploit the inherent specificity in each genetic network - whether it be a microbial pathogen, a cancer cell, or an inherited disorder - to develop rational combinations of chemicals that selectively alter any given pathogenic or disease network.

There is a pressing need for new antifungal drug because patients with suppressed immune systems are very susceptible to fungal infections, for example after organ transplants, cancer chemotherapy or HIV infection. However, there are very few nontoxic drugs that can be used to kill these fungal pathogens. Moreover, resistance to widely used anti-fungal drugs threatens millions of immuno-compromised patients susceptible to invasive fungal infections. A main focus of our program has therefore been to explore combinations of compounds that selectively target fungal pathogens.

We have developed methods to combine compounds resulting in highly targeted approaches towards fungal pathogens. These combinations have the potential to act as novel combination therapies. We carried out systematic screens with off-patent drugs to identify compounds that potentiate fluconazole activity in pathogenic yeast strains. Many compound combinations exhibited species-specific activity, and often improved the killing characteristics of anti-fungal agents and were active against resistant clinical isolates. The same approach has been applied to bacterial pathogens to reveal new non-toxic combinations of known drugs with powerful antibiotic activity that are also active against human pathogens. In parallel, we have assembled libraries of thousands of bioactive chemicals, screened these libraries against many hundreds of genetic backgrounds to create a matrix of chemical-gene interactions, and then developed algorithms to predict combinations of compounds that exhibit synergistic activities against different pathogens. These rational combinations offer several potential benefits compared to conventional single drugs, including more potent activity, fewer side effects and lower susceptibility to the emergence of drug resistance.

We have also developed a custom bioactive chemical library which we then tested for various activities against different species, including other yeasts, worms, fish, plants and human cells. This study has shown that chemicals can exhibit activity against all species but can often also show species-specific activity. These compounds have proven useful to understand new aspects of biological function in yeast, nematodes, plants, fish and humans. For example, we have identified a new mechanism that controls the proliferation of the melanocytes that cause pigmentation of the skin, deciphered mechanisms of off-target drug effects, and identified new potential anti-cancer agents.

We have also screened known drugs for the ability to control the self-renewal of human neuronal stem cells and brain tumour stem cells. This approach has identified chemicals that stimulate the development of stem cells into different cell types, as well as specific inhibitors of brain tumour stem cells. The systematic repurposing of approved drugs can thus identify network vulnerabilities that may be exploited for therapeutic benefit in many disease states.

These various approaches have relied on sophisticated computer models of chemical-genetic network activity, which we have made available as public resources for use by the international research community.

In summary, our ERC research program has enabled new potential approaches to drug discovery, based on combinations of chemicals that exploit natural genetic networks. This combinatorial approach to control biological responses has many potential applications in human disease, including infection, cancer, diabetes, immune disorders and regenerative medicine.