Fluorothiazinon, a small-molecular inhibitor of T3SS, suppresses salmonella oral infection in mice
| Autor: | D. V. Balunets, Anna B. Sheremet, Nesterenko Ln, Alexandr L Gintsburg, Egor S. Zayakin, Sergey I Luyksaar, Zigangirova Na, Anna V Soloveva |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Pharmacology Salmonella biology 010405 organic chemistry Pseudomonas aeruginosa business.industry 030106 microbiology Virulence Salmonella infection medicine.disease_cause medicine.disease biology.organism_classification 01 natural sciences 0104 chemical sciences Microbiology 03 medical and health sciences medicine.anatomical_structure In vivo Salmonella enterica Drug Discovery medicine Mesenteric lymph nodes business Pathogen |
| Zdroj: | The Journal of Antibiotics. 74:244-254 |
| ISSN: | 1881-1469 0021-8820 |
| DOI: | 10.1038/s41429-020-00396-w |
| Popis: | Therapeutic strategies that target bacterial virulence have received considerable attention. The type III secretion system (T3SS) is important for bacterial virulence and represents an attractive therapeutic target. Recently, we developed a new small-molecule inhibitor belonging to a class 2,4-disubstituted-4H-[1,3,4]-thiadiazine-5-ones, Fluorothiazinon (FT—previously called CL-55). FT effectively suppressed T3SS of Chlamydia spp., Pseudomonas aeruginosa, and Salmonella without affecting bacterial growth in vitro. FT was previously characterized by low toxicity, stability, and therapeutic efficacy in animal models. Salmonella T3SS inhibition by FT was studied using in vitro assays for effector proteins detection and estimation of salmonella replication in peritoneal macrophages. The antibacterial effect of FT in vivo was investigated in murine models of salmonella chronic systemic and acute infection. Oral administration of the virulent strain of Salmonella enterica serovar Typhimurium to mice-induced chronic systemic infection with the pathogen persistence in different lymphoid organs such as spleens, Peyer’s plaques, and mesenteric lymph nodes. We found that FT suppressed orally induced salmonella infection both with therapeutic and prophylactic administration. Treatment by FT at a dose of 50 mg/kg for 4 days starting from day 7 post-infection (therapy) as well as for 4 days before infection (prevention) led to practically complete eradication of salmonella in mice. FT shows a strong potential for antibacterial therapy and could be used as a substance in the design of antibacterial drugs for pharmaceutical intervention including therapy of antibiotic-resistant infections. |
| Databáze: | OpenAIRE |
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