Identification of chlamydial T3SS inhibitors through virtual screening against T3SS ATPase
| Autor: | A. V. Grishin, Lidiya N. Kapotina, Zigangirova Na, Dmitry D. Kirsanov, Anna S. Karyagina, Sergey I Luyksaar, Egor S. Zayakin |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
030106 microbiology Drug Evaluation Preclinical Chlamydia trachomatis Vacuole Biology medicine.disease_cause Biochemistry Type three secretion system Microbiology Cell Line 03 medical and health sciences Bacterial Proteins Drug Discovery medicine Type III Secretion Systems Humans Enzyme Inhibitors Pathogen Pharmacology Adenosine Triphosphatases Chlamydia Effector Organic Chemistry Chlamydia Infections medicine.disease Virology Anti-Bacterial Agents Chronic infection 030104 developmental biology Host cell cytoplasm Molecular Medicine |
| Zdroj: | Chemical biologydrug design. 91(3) |
| ISSN: | 1747-0285 |
| Popis: | 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. Chlamydia rely upon type III secretion system (T3SS) to inject effector proteins into host cell cytoplasm, and T3SS inhibitor 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 modelled 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 2 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 towards eukaryotic cells. A small series of derivatives was further synthesized for the most active of two inhibitors to probe SAR properties. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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