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Published on: October 25, 2019
Identification of chlamydial T3SS inhibitors through virtual screening against T3SS ATPase
Alexander V Grishin1,2, Sergey I Luyksaar1, Lidiya N Kapotina1
1N.F. Gamaleya National Research Center of Epidemiology and Microbiology, Moscow, Russia.
Abstract:
Chlamydia trachomatis is a widespread sexually transmitted pathogen that resides within a special vacuole inside host cells. Although acute infection can be treated with antibiotics, chlamydia can enter persistent state, leading to chronic infection that is difficult to cure. Thus, novel anti-chlamydial compounds active against persistent chlamydia are required. Chlamydiae rely upon type III secretion system (T3SS) to inject effector proteins into host cell cytoplasm, and T3SS inhibitors are viewed as promising compounds for treatment of chlamydial infections. C. trachomatis ATPase SctN is an important T3SS component and has not been targeted before. We thus used virtual screening against homology modeled SctN structure to search for SctN inhibitors. Selected compounds were tested for their ability to inhibit chlamydial survival and development within eukaryotic cells, and for the ability to suppress normal T3SS functioning. We identified two compounds that were able to block normal protein translocation through T3SS and inhibit chlamydial survival within eukaryotic cells in 50-100 μm concentrations. These two novel T3SS inhibitors also possessed relatively low toxicity toward eukaryotic cells. A small series of derivatives was further synthesized for the most active of two inhibitors to probe SAR properties.
Insights
Novel compounds targeting Chlamydia trachomatis ATPase SctN show promise for treating persistent infections. These type III secretion system (T3SS) inhibitors block bacterial survival and protein translocation with low toxicity.
Area of Science:
- Microbiology
- Infectious Diseases
- Drug Discovery
Background:
- Chlamydia trachomatis causes widespread sexually transmitted infections, often leading to difficult-to-cure chronic states.
- Current antibiotics are ineffective against persistent chlamydial infections, necessitating novel therapeutic strategies.
- The type III secretion system (T3SS) is crucial for chlamydial pathogenesis and represents a potential therapeutic target.
Purpose of the Study:
- To identify novel inhibitors of the Chlamydia trachomatis type III secretion system (T3SS).
- To specifically target the T3SS ATPase SctN, a previously unexploited component.
- To evaluate the efficacy of identified compounds against persistent chlamydial infections in eukaryotic cells.
Main Methods:
- Virtual screening of homology-modeled SctN structure to identify potential inhibitors.
- In vitro testing of selected compounds for inhibition of chlamydial survival and development.
- Assessment of compounds' ability to block T3SS protein translocation and eukaryotic cell toxicity.
Main Results:
- Two novel compounds were identified that inhibit T3SS protein translocation and chlamydial survival at 50-100 μm concentrations.
- These compounds demonstrated low toxicity to eukaryotic cells.
- Structure-activity relationship (SAR) studies were initiated for the most potent inhibitor.
Conclusions:
- Novel T3SS inhibitors targeting SctN offer a promising avenue for developing new treatments against persistent Chlamydia trachomatis infections.
- The identified compounds effectively inhibit chlamydial pathogenesis with a favorable safety profile.
- Further development of these inhibitors could lead to effective therapies for chronic chlamydial diseases.
