Rapid Inhibitor Discovery by Exploiting Synthetic Lethality

Synthetic lethality occurs when inactivation of two genes is lethal but inactivation of either single gene is not. This phenomenon provides an opportunity for efficient compound discovery. Using differential growth screens, one can identify biologically active compounds that selectively inhibit proteins within the synthetic lethal network of any inactivated gene. Here, based purely on synthetic lethalities, we identified two compounds as the only possible inhibitors of Staphylococcus aureus lipoteichoic acid (LTA) biosynthesis from a screen of similar to 230,000 compounds. Both compounds proved to inhibit the glycosyltransferase UgtP, which assembles the LTA glycolipid anchor. UgtP is required for beta-lactam resistance in methicillin-resistant S. aureus (MRSA), and the inhibitors restored sensitivity to oxacillin in a highly resistant S. aureus strain. As no other compounds were pursued as possible LTA glycolipid assembly inhibitors, this work demonstrates the extraordinary efficiency of screens that exploit synthetic lethality to discover compounds that target specified pathways. The general approach should be applicable not only to other bacteria but also to eukaryotic cells.

Automated summary

This study utilized synthetic lethality screening to identify two compounds that effectively inhibit the biosynthesis of Staphylococcus aureus lipoteichoic acid (LTA). These compounds were shown to restore sensitivity to oxacillin in a highly resistant S. aureus strain by targeting the glycosyltransferase UgtP. The study highlights the efficiency of using synthetic lethality to discover compounds that target specific pathways and suggests broader applications in other bacteria and eukaryotic cells.