Grant: Project Grant

Many of the drugs and medicines that we rely on today are natural products, made by the earth's flora. Important classes of these compounds are made in fungi and bacteria by massive enzymes called nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs), or by fusions of these enzymes (PKS-NRPSs). They synthesize all sorts of antibiotics, which can kill dangerous fungi and bacteria, as well as compounds to help us fight off viral infections and cancers. For example, these compounds include viomycin, an antibiotic used for the treatment of multidrug-resistant tuberculosis; cyclosporin, which has been widely used as an immunosuppressant in organ transplants and can inhibit hepatitis virus C replication; and the familiar antibiotic penicillin. The goal of this research is to expand our knowledge of NRPSs, PKSs, and NRPS-PKSs and the mechanisms they employ to synthesize important drugs. We will use biochemistry and biophysics, including techniques known as X-ray crystallography and cryo-electron microscopy, to capture three-dimensional pictures of an NRPS or PKS at different points in the process of making these natural products. We will answer questions ranging from how, in a natural hybrid fusion of one kind of enzyme (PKS) and the other (NRPS), the separate parts can function together, to how a domain normally found in a PKS has adapted to work in an NRPS, to how the last step of synthesis, common to both NRPSs and PKSs, releases the molecule in its proper, active form. These enzymes have excellent potential to produce new therapeutics. They are divided into segments called modules, where each module adds one building block to form the product. If we have enough knowledge of the enzymes, we should be able to switch around the order of the modules to produce variants of the current therapeutics. Our studies can help understand how to make new compounds which may be able to fight antibiotic resistant bacteria, viruses and cancer.