Nesterenko Ludmila N, Zigangirova Nailya A, Zayakin Egor S, Luyksaar Sergey I, Kobets Natalie V, Balunets Denis V, Shabalina Ludmila A, Bolshakova Tatiana N, Dobrynina Olga Y, Gintsburg Alexander L
Gamaleya Research Center for Epidemiology and Microbiology, Moscow, Russia.
J Antibiot (Tokyo). 2016 Jun;69(6):422-7. doi: 10.1038/ja.2015.131. Epub 2016 Jan 6.
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.
针对细菌毒力的治疗策略已受到广泛关注。III型分泌系统（T3SS）对细菌毒力至关重要，是一个有吸引力的治疗靶点。一种名为CL-55（N-(2,4-二氟苯基)-4-(3-乙氧基-4-羟基苄基)-5-氧代-5,6-二氢-4H-[1,3,4]-噻二嗪-2-甲酰胺）的新型化合物，此前已被证明具有低毒性、高溶解度、稳定性以及在体外和体内对沙眼衣原体的特异性作用效率。在本研究中，我们描述了CL-55对鼠伤寒沙门氏菌的作用。我们发现CL-55不影响鼠伤寒沙门氏菌的体外生长，但能抑制其体内感染。以10 mg kg(-1)的剂量腹腔注射CL-55，连续4天，可显著（500倍）降低脾脏和腹腔灌洗液中沙门氏菌的数量，并提高易感（BALB/c、I/St）和抗性（A/Sn）小鼠的存活率。12天的治疗可使小鼠体内的沙门氏菌完全清除。此外，治疗后4 - 6周未发现病原体。CL-55无致癌或致突变性，不会增加骨髓细胞中的染色体畸变水平，且在小鼠、大鼠和兔子中具有低毒性。药代动力学研究表明，CL-55能迅速从体循环中消失并分布于各器官。我们的数据表明，CL-55在体内对鼠伤寒沙门氏菌有作用，可作为设计用于细菌毒力感染药物干预的抗菌抑制剂的一种物质。
