Rapid Inhibitor Discovery by Exploiting Synthetic Lethality

Abstract

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 ∼230,000 compounds. Both compounds proved to inhibit the glycosyltransferase UgtP, which assembles the LTA glycolipid anchor. UgtP is required for β-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.

Insights into the Roles of Lipoteichoic Acids and MprF in Bacillus subtilis

“…Analyses of LTA synthesis and the cell wall composition of MRSA clinical isolates will help verify our MprF-mediated Dap R mechanism and help appreciate the role of MprF in the net cell surface charge and protection against cationic antimicrobial peptides. Our results also give support to the practical application of compounds targeting LTA synthesis ( 68 , 69 ) and MprF-targeting monoclonal antibodies ( 70 ) as approaches to treat clinically relevant bacteria.…”

MultiCPA: Multimodal Compositional Perturbation Autoencoder

“…We anticipate MultiCPA to guide exploration of the perturbation space, leading to the development of novel therapeutics (Brochado et al, 2018), and facilitating the discovery of the general principles of a cellular machinery (Muscato et al, 2022) in biological research. As future directions, we aim to extend our model with other cellular modalities, such as chromatin accessibility data by scATAC-seq (Lareau et al, 2019; Lotfollahi et al, 2022) technology.…”

Antibiotic Adjuvants: A Versatile Approach to Combat Antibiotic Resistance

“… 142 By the employment of synthetic lethality networks and differential growth screens, two lipoteichoic acid (LTA) synthesis inhibitors ( 41 and 42 ) were identified which inhibit the glycosyltransferase, UgtP, involved in the assembly of an LTA glycolipid anchor. 143 These inhibitors restored activity to oxacillin in resistant strains of MRSA. Another study modeled the binding of an inhibitor 1771-bound LtaS structure and used this model for virtual screening of new molecular scaffolds for LtaS inhibition.…”

“…Unlike wall teichoic acids, which are dispensable to cellular survival, lipoteichoic acids play a key role in the bacterial cell division process, and inhibition of its synthesis can impair the cell division machinery . By the employment of synthetic lethality networks and differential growth screens, two lipoteichoic acid (LTA) synthesis inhibitors ( 41 and 42 ) were identified which inhibit the glycosyltransferase, UgtP, involved in the assembly of an LTA glycolipid anchor . These inhibitors restored activity to oxacillin in resistant strains of MRSA.…”