CRISPRi meets metabolomics: a platform for rapid functional annotation of compound libraries

While the rapid emergence of antibiotic-resistant bacteria raises an urgent need for antimicrobials with new Modes of Action, their discovery remains a major challenge. Many of the techniques to unravel drug Modes of Action rely on low-throughput, time-consuming and target-specific approaches that provide low-dimensional views into the broader functional impact of potential drugs. The Zampieri lab (@ZampieriLab) at ETH, by leveraging CRISPR technology and non-targeted metabolomics, proposed a combined computational/experimental strategy that is based on the comparison of genetic and drug induced metabolic effects thereby allowing to perform high-throughput de novo functional annotations of large compound libraries.

The methodology was developed in a collaborative effort with research teams at ETH, the Biozentrum of the University of Basel, Albert Einstein College of Medicine and was funded by @NCCR_AntiResist. It represents a new strategy to rapidly and systematically assess functional properties of large numbers of small molecules. Unraveling the mechanistic basis of drug perturbations of thousands of metabolites provides rich multidimensional information complementary to classical phenotypic profiling and can be used to investigate the effect and mode of action of any drug candidate. The authors demonstrate the efficacy of this new approach not only in the discovery and characterization of antimicrobials, but also demonstrated that the same approach can be used to tackle fundamental bottlenecks in drug development and discovery across many diverse therapeutic areas, including cancer.

Link to the paper in external page Nature Chemical Biology