Grant: Operating Grant

Many of the drugs and medicines that we rely on today are so-called natural products, made by the earth's flora and fauna. One important class of these compounds is made by fungi and bacteria using massive enzymes called nonribosomal peptide synthetases (NRPS). 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. 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 penicillin, the famous antibiotic. The goal of this research is to expand our knowledge of NRPSs and the mechanisms they employ to synthesize important drugs. I will use biochemistry and biophysics, including techniques known as X-ray crystallography and cryo-electron microscopy, to capture three-dimensional pictures of an NRPS at different points in the process of making these antibiotics. I will study several NRPSs, including the penicillin synthesizing enzyme and the cyclosporin synthesizing enzyme, but the results of the work will be applicable to all NRPSs. The subjects addressed will range from elucidating the precise details of how building blocks are chemically assembled into the antibiotics, to understanding the large-scale rearrangements these enzymes need to perform to these drugs. NRPSs hold a vast potential to produce new drugs. Because NRPSs are divided into segments, with each segment adding one building block to the drug, we can switch around the order and specific type of segment to produce variants of the drug. My studies can help us learn how best to re-arrange NRPS segments to make millions of new compounds. Among these compounds could be important drugs to fight antibiotic resistant bacteria, viruses and cancer.