Grant: Project Grant

Many life-saving medicines are made naturally by earth's plants and microbes. An important class of microbial compounds is made using three types of massive megaenzymes: nonribosomal peptide synthetases, polyketide synthases, and "hybrid" fusions of these two partners. Hybrid megaenzymes synthesize a wide range of antibiotics which kill dangerous fungi and bacteria, as well as compounds that can help fight off viral infections and cancers. Examples of hybrid natural products include rifampin, an antibiotic used against bacterial infections like tuberculosis and Legionnaires' disease; bleomycin, a front-line medication against lymphoma and other cancers; and tacrolimus and rapamycin, potent immunosuppressants used in organ transplants. The goal of this research is to expand our knowledge of hybrid megaenzyme systems to understand the mechanisms they use to synthesize important drugs. We will use many techniques in biochemistry, chemical biology, biophysics and structural biology to capture 3D images of hybrid megaenzymes at different points in the process of making their bioactive natural products. We will answer questions ranging from how the natural hybrid fusions allow the two parts to work together, to how the last step of synthesis common to most megaenzymes works, to how associated enzymes can put the finishing touches on some compounds to make the final bioactive compound. Hybrid megaenzymes have exciting potential to produce new therapeutics. They are organised into sub-sections called modules, where each module adds one building block to the product. If we have enough knowledge of the enzymes, we should be able to switch around the order of the modules to produce next-gen variants of current therapeutics. Our studies can help understand how to make new compounds to fight cancer, fungi and antibiotic-resistant bacteria.