Visualizing A Natural Antibiotic Nanofactory

Environmental samples are excellent sources of natural products that possess numerous kinds of therapeutic activities. One important family of natural products is the nonribosomal peptides, which includes penicillin, cyclosporin, viomycin and daptomycin (Cubicin). These peptides are made in bacteria or fungi by large enzymes called nonribosomal peptide synthetases (NRPS). NRPSs are true macromolecular machines or nanofactories, with modular assembly-line logic, a complex catalytic cycle, moving parts and many active sites. Visualization of large fragments of NRPSs at various functional states is required to understand the manner in which NRPSs synthesize their important products. Many excellent structural experiments have been performed to date. Recently, we added to the structural knowledge by visualizing the first module of the NRPS, which makes linear gramicidin, a clinical topical antibiotic, in all its major functional states. These experiments show how the individual domains, including an unusual tailoring domain, function together in assembly-line synthesis. Along with the ever-expanding body of biophysical, biochemical and genetic work, this work brings us closer to a fundamental understanding of these natural antibiotic nanofactories, and perhaps the ability to exploit them to produce novel therapeutics.