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Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells

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Rapid Inhibitor Discovery by Exploiting Synthetic Lethality.

Jacob D Muscato¹, Heidi G Morris¹, Aaron Mychack¹

¹Department of Microbiology, Harvard University, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.

Journal of the American Chemical Society

|February 16, 2022

Summary

Synthetic lethality enables efficient drug discovery. Researchers identified two compounds targeting Staphylococcus aureus lipoteichoic acid (LTA) biosynthesis, restoring antibiotic sensitivity in resistant strains.

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Area of Science:

Microbiology
Drug Discovery
Synthetic Lethality

Background:

Synthetic lethality is a powerful strategy for identifying essential gene interactions and potential drug targets.
Identifying compounds that inhibit essential bacterial pathways is crucial for combating antibiotic resistance.

Purpose of the Study:

To leverage synthetic lethality for the discovery of novel inhibitors of Staphylococcus aureus lipoteichoic acid (LTA) biosynthesis.
To identify compounds targeting the glycosyltransferase UgtP, essential for LTA assembly.

Main Methods:

Conducted differential growth screens of approximately 230,000 compounds.
Utilized synthetic lethality principles to identify compounds selectively inhibiting proteins in essential pathways.
Assayed compound activity against UgtP and its role in LTA biosynthesis.

Main Results:

Identified two novel compounds as the sole inhibitors of LTA biosynthesis from the screened library.
Both compounds were found to inhibit the UgtP glycosyltransferase.
Inhibitors restored oxacillin sensitivity in a highly methicillin-resistant Staphylococcus aureus (MRSA) strain.

Conclusions:

Screens exploiting synthetic lethality are highly efficient for discovering pathway-specific inhibitors.
The identified UgtP inhibitors represent a promising new avenue for combating MRSA infections.
This approach is broadly applicable to bacterial and eukaryotic drug discovery.