Grant: Foundation Grant

Very many clinically-used therapeutics are produced naturally by earth's flora and fauna. They are often made in microbes by huge enzymes called nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs). Examples include daptomycin, used against MRSA superbugs; viomycin, used to treat multidrug-resistant tuberculosis; actinomycin D, used to fight cancers like Wilms tumor; cyclosporin, which was widely used as an immunosuppressant in organ transplants and can also inhibit the hepatitis C virus; and penicillin. A frequent target of natural compounds is another megaenzyme, the ribosome. The ribosome makes proteins in all cells. Inhibiting the ribosome in bacterial cells can kill bacteria and cure infections. The goal of this research is to expand our knowledge of how megaenzymes make important natural drugs and how megaenzyme-made drugs act on the ribosome. Using biochemistry and biophysics, we will analyze NRPSs and PKSs and capture 3D pictures of them at different points in the process of making natural products. We will also capture 3D pictures of natural products bound to and inhibiting the ribosome. This enables us to answer a range of questions, elucidating the details of how building blocks are chemically assembled into the antibiotics, explaining the large rearrangements NRPSs need to perform to create drugs and revealing new ways that natural drugs work against the ribosome. Megaenzymes hold a vast potential to produce new drugs. Because NRPSs and PKSs are divided into segments, with each segment adding one building block to the drug, we can alter the order of segments and the specific types of segment to produce variants of the drug product. For some drugs, we will visualize what each building block is doing to the ribosome. Our studies can help us learn how best to rearrange NRPS segments to make millions of new compounds, to better kill antibiotic resistant bacteria and also to fight other challenges to human health like viruses and cancer.