Institute of Molecular Systems Biology, ETH Zurich Zurich, SWITZERLAND

Wednesday 21 October 2020 |12:00 noon – ICGEB Trieste, ITALY

High-throughput functional annotation of compound libraries using metabolic fingerprints

Host: L. Banks

Despite rapid technological progress, the discovery of novel antibiotics has been stalled for the past 50 years. To c ombat the grow i n g b u r d e n of antibioticresistance , i n n o v a t i v e d r u g d i s c o v e r y p a r a d i g m s are required to improve and expedite the antibiotic discovery process. A crucial bottleneck in drug discovery is the identification of compounds’ Mode of Action (MoA). To address this problem we developed a rapid and systematic metabolome profiling strategy to classify the MoA of bioactive compounds. In contrast to existing methods based on phenotypic drug profiling, mostly on the basis of growth assays, we exploit here the intracellular response of about 1000 metabolites as a truly multiparametric readout of the cellular response. The specific advance over existing metabolic platforms is a faster throughput of 1-2 orders of magnitude, allowing our combined MS-based metabolomics and computational workflow to scale with the size of typical compound libraries. I will illustrate how this technology enables monitoring the metabolic response of Escherichia coli to 1279 human targeted drugs and revealed an unexpectedly large spectrum of metabolic effects in E. coli. Combining metabolic profiling with chemogenomic data, we predicted drug MoAs and epistatic drug interactions. Our approach opens new opportunity in systems pharmacology and reveals new ways to expand the search for new antimicrobial treatments to compounds with no growth-inhibitory activity. Moreover, we I will introduce how a similar framework can be adapted and applied as a general strategy in anticancer discovery.