Hijacking thiocillin biosynthesis to build new antibiotics

With the emergence of life-threatening drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE), the need for new antibiotics is greater than ever. Yet, the development of new antibiotics has remained stagnant for nearly 50 years.  A promising class of natural products, called thiopeptides, inhibits the growth of these gram-positive bacteria at nanomolar concentrations.  Thiopeptides are exciting as potential antibiotics, because their site of action, the interface between ribosomal protein L11 and 23S rRNA, is distinct from all existing classes of antibiotics.  Importantly, these natural products are derived from genetically encoded peptides, which allows for the generation of new thiopeptide analogs by simple mutagenesis.  The goal of this project is to develop a continuous and genetically encoded source of new antibiotics against drug-resistant bacterial pathogens by combining the power of recombinant DNA technology with the biosynthesis of natural product antibiotics.  If successful, this project will have a significant impact on public health because the development of new antibiotic drugs is necessary to combat the rising problem of emerging drug resistance. Moreover, it will lay the groundwork for generating a new diverse class of natural products to screen for many other therapeutic applications.