Resolving the Bottleneck in Antibiotic Discovery

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The goal of this multicomponent project is to develop an efficient transcriptomic approach to dereplicate antibacterial extracts of pure isolates of uncultured soil bacteria, revealing which are chemically identical to known antibiotics. Leveraging our expertise in transcriptomics at JCVI and in collaboration with Dr. Kim Lewis (Northeastern University) and Dr. Amy Spoering (NovoBiotic), we will develop an effective discovery program based on exploiting uncultured bacteria to resolve the bottleneck of antimicrobial drug discovery. Uncultured bacteria are an untapped source of secondary metabolites, and our collaborators developed methods to grow them and mine for antibiotic discovery. However, the real potential of uncultured bacteria remains unrealized - the background of knowns and toxic compounds has been the main bottleneck even for this untapped source of chemical diversity. We propose to solve this problem by introducing transcriptome analysis as a rapid tool to identify promising compounds from uncultured bacteria. Compounds affecting the same target produce distinct transcription profiles that cluster together. This approach allows us to classify compounds as known; novel hitting a known target; novel hitting a new valuable target; hitting an undesirable target; or a nuisance compound lacking specificity.

We are generating a database of transcription profiles from known antimicrobials, develop effective computational tools for transcriptome analysis, and will interrogate transcriptomes from a large number of extracts and their fractions from uncultured bacteria. This approach quickly and inexpensively provides the potential to find novel antimicrobials from new sources without wasting time and resources on already known antibacterial compounds. The approach will aid in the identification of candidate modes of action (MOAs) of any novel compounds and will suggest that a compound is exhibiting a potential new MOA and target where a known MOA is not suggested by the analysis. Our goal is to resolve the dereplication bottleneck in natural product antibacterial drug discovery.

Funding for this project provided by the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), NIH-NIAID P01 award (5P01AI118687).