Grant: Operating Grant

Many of the medicines on which we rely today are produced naturally by earth's flora and fauna. An important class of these compounds is made in fungi and bacteria by massive enzymes called nonribosomal peptide synthetases (NRPSs). NRPSs synthesize all sorts of antibiotics, which can kill dangerous fungi and bacteria, as well as compounds that can help us fight off viral infections and cancers. NRPS products include the antibiotic viomycin, used to treat multidrug-resistant tuberculosis; cyclosporin, widely used as an immunosuppressant in organ transplants, which can also inhibit hepatitis virus C replication; and penicillin. The goal of this research is to expand our knowledge of NRPSs and the mechanisms they employ to synthesize important compounds. We will use biochemistry and biophysics, including techniques known as X-ray crystallography and cryo-electron microscopy, to capture three-dimensional pictures of NRPSs at different points in the process of making these natural products. We will study several NRPSs, including the penicillin synthesizing enzyme, and the results of the work will be applicable to all NRPSs and their products. We will answer a range of questions, elucidating the precise details of how building blocks are chemically assembled into the antibiotics, and explaining the large-scale rearrangements these enzymes need to perform to create drugs. NRPSs hold a vast potential to produce new therapeutics. Because NRPSs are divided into segments, with each segment adding one building block to the compound, we can switch around the order and specific type of segment to produce variants of the compound. Our studies can help us learn how best to rearrange NRPS segments to make millions of new compounds. Among these compounds could be important drugs to fight viruses, antibiotic resistant bacteria, and cancer.