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A Cell-based Screen in Actinomyces oris to Identify Sortase Inhibitors
Jason E Gosschalk1,2, Chungyu Chang3, Christopher K Sue1,2
1Department of Chemistry and Biochemistry, University of California, Los Angeles, USA.
Scientific Reports
|May 24, 2020
Summary
This study introduces a new cell-based screen using Actinomyces oris to find sortase inhibitors. This method effectively identifies molecules that disrupt bacterial surface proteins and inhibit enzyme activity in whole cells.
Area of Science:
- Microbiology
- Drug Discovery
- Enzymology
Background:
- Sortase enzymes are crucial for virulence in pathogens like Staphylococcus aureus.
- Existing methods for sortase inhibitor discovery use in vitro assays, limiting in vivo relevance.
- Developing novel antivirulence strategies targeting sortases is a significant medical need.
Purpose of the Study:
- To develop and implement a novel cell-based high throughput screening (HTS) method for identifying sortase inhibitors.
- To discover inhibitors effective in inactivating sortases in vivo.
- To utilize Actinomyces oris as a model organism for sortase inhibitor discovery.
Main Methods:
- A cell-based screen was developed using Actinomyces oris, which exhibits sortase-dependent growth.
- High throughput screening (HTS) was employed to identify molecules impacting cellular growth.
- Identified compounds were further tested for their ability to disrupt surface protein display and inhibit enzyme activity in vitro.
Main Results:
- Three novel molecules, belonging to two distinct scaffolds, were identified through HTS.
- These molecules were shown to disrupt surface protein display in intact Actinomyces oris cells.
- The identified compounds also demonstrated inhibition of sortase enzyme activity in vitro.
Conclusions:
- Actinomyces oris provides a robust platform for HTS of sortase inhibitors based on cellular growth.
- This study represents the first HTS for sortase inhibitors utilizing a cellular growth phenotype.
- The discovered molecules are promising candidates for further development as antivirulence drugs targeting sortase enzymes.
