Abstract
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. A novel compound with a predicted T3SS inhibitory activity named CL-55 (N-(2,4-difluorophenyl)-4-(3-ethoxy-4-hydroxybenzyl)-5-oxo-5,6-dihydro-4H-[1,3,4]-thiadiazine-2-carboxamide) was previously characterized by low toxicity, high levels of solubility, stability and specific efficiency toward Chlamydia trachomatis in vitro and in vivo. In this study, we describe the action of CL-55 on Salmonella enterica serovar Typhimurium. We found that CL-55 does not affect Salmonella growth in vitro but suppresses Salmonella infection in vivo. The i.p. injection of CL-55 at a dose of 10 mg kg−1 for 4 days significantly (500-fold) decreased the numbers of Salmonella in the spleen and peritoneal lavages and increased the survival rates in susceptible (BALB/c, I/St) and resistant (A/Sn) mice. Twelve days of therapy led to complete eradication of Salmonella in mice. Moreover, no pathogen was found 4–6 weeks post treatment. CL-55 was not carcinogenic or mutagenic, did not increase the level of chromosomal aberrations in bone marrow cells and had low toxicity in mice, rats and rabbits. Pharmacokinetic studies have shown that CL-55 rapidly disappears from systemic blood circulation and is distributed in the organs. Our data demonstrates that CL-55 affects S. enterica serovar Typhimurium in vivo and could be used as a substance in the design of antibacterial inhibitors for pharmaceutical intervention of bacterial virulence for infection.
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This work was supported by grants from the Russian Ministry of Science and Education and the Russian Ministry of Industry.
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Nesterenko, L., Zigangirova, N., Zayakin, E. et al. A small-molecule compound belonging to a class of 2,4-disubstituted 1,3,4-thiadiazine-5-ones suppresses Salmonella infection in vivo. J Antibiot 69, 422–427 (2016). https://doi.org/10.1038/ja.2015.131
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DOI: https://doi.org/10.1038/ja.2015.131
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