Project I: Abstract The overall goal of the Program project is to develop a discovery platform for antimicrobials based on early validation of extracts to resolve the bottleneck in the pipeline and realize the true potential of uncultured bacteria as a source of novel drugs. We have used in situ cultivation to gain access to uncultured bacteria, and so far discovered 25 new compounds, including 4 in development - Novo10, a G-quadruplex binder, in development as an anticancer agent; lassomycin, an inhibitor of the essential M. tuberculosis ClpP1P2C1 protease; teixobactin, a novel inhibitor of cell wall biosynthesis that binds to both lipid II, precursor of peptidoglycan, and lipid III, precursor of teichoic acid, and Novo22, another novel cell wall synthesis inhibitor. While these findings are encouraging, most of the effort is spent on laborious chemical dereplication. In collaboration with Dr. Karen Nelson at JCVI (Project II), we will use metagenomic analysis to select soils with novel species likely to harbor novel chemistry, apply our technologies to isolate previously uncultivated microorganisms and use transcriptome analysis of extracts to develop rapid biological dereplication. This will indicate the potential of a compound for development and will resolve the discovery bottleneck. We will purify the hits and will determine the structure for those that pass in vitro and in vivo validation (in collaboration with Dr. Kim Lewis, Project III). The result of this project will be an efficient drug discovery platform for exploiting uncultured bacteria; and leads for drug development.
Project I: Narrative There is a looming human health crisis caused by the spread of drug-resistant pathogens. We will develop a new platform for discovering effective antibiotics by exploiting an untapped source ? uncultured bacteria, combined with an effective method to decide early on if a compound has potential value by identifying its mode of action.
