Grant: Project Grant

The world desperately needs new medicines to treat evasive human pathogens. Each year, 1.5 million (M) people die from tuberculosis, 1M die from mosquito-borne diseases, 0.2M die from blood flukes, 1M lose their vision from river blindness, and hospitals are increasingly riddled with drug-resistant bacterial and fungal infections. These diseases still kill people because of a lack of effective drugs. Here, we present a novel, fast, and efficient technology that enables the discovery of new candidate drugs to target these diseases. Our previous work revealed a group of small molecules that kill worm parasites in a novel way. These molecules only become lethal when they are converted into lethal products by an enzyme called cytochrome p450 (CYP). Importantly, when we express the worm CYPs in baker's yeast, our new molecules can kill the yeast in a worm CYP-dependent way. These results led us to the idea that we can express CYPs from many different pathogens in yeast and then screen for molecules that kill specific yeast strains in a CYP-dependent manner. Here, we describe how we will use our new technology to identify new candidate drugs. We will build a library of yeast strains in which each strain expresses a distinct CYP from humans, drug-resistant and difficult-to-treat bacteria, fungi, parasites or mosquitos. We pool these strains together and screen the entire pool at once against 1000s of candidate new drugs. DNA sequencing technology is used to identify which yeast strain within the pool dies in response to which candidate drug. Molecules that kill yeast strains expressing pathogenic (but not human) CYPs are further prioritized with tests against the pathogens themselves. Our new drug discovery technology has immense power by targeting 25 of the world's most dangerous human pathogens in parallel. It will yield new drug leads and new drug targets, all of which will contribute to the development of new medicines to treat evasive human pathogens.