Impact on toxin production and cell morphology in Clostridium difficile by ridinilazole (SMT19969), a novel treatment for C. difficile infection.
Impact on toxin production and cell morphology in Clostridium difficile by ridinilazole (SMT19969), a novel treatment for C. difficile infection.
复制标题
DOI：
10.1093/jac/dkv498
复制
发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Garey KW
中科院分区：
文献类型：
--
作者：
Bassères E;Endres BT;Khaleduzzaman M;Miraftabi F;Alam MJ;Vickers RJ;Garey KW
利地尼唑（SMT 19969）是一种窄谱、不可吸收的抗菌剂，对正在进行临床试验的艰难梭菌具有活性。本研究的目的是评估吡啶尼唑的药理活性和评估对细胞形态的影响。使用流行性C.艰难梭菌核糖体型027菌株R20291，使用超MIC（4×和40×）和亚MIC（0.125×、0.25×和0.5×）浓度的吡啶咪唑。暴露后，C.收集艰难梭菌细胞用于cfu计数、毒素A和B产生以及使用扫描电子和荧光显微镜观察形态学变化。将人肠细胞（Caco-2）与吡啶咪唑处理的C. difficile生长培养基中培养以确定对宿主炎症反应（IL-8）的影响。与不诱导孢子形成的对照组相比，在超MIC浓度（4×和40× MIC）的吡啶尼唑处理72 h后，营养细胞显著减少（4 log差异，P <0.01）。 这些结果与毒素A产生减少75%（P <0.05）和毒素B产生减少96%（P <0.05）相关。 在亚MIC水平（0.5× MIC）下，毒素A的产生减少了91%（P <0.01），毒素B的产生减少了100%（P <0.001），这导致与对照相比IL-8释放减少了74%（P <0.05）。 亚MIC（0.5×）处理的细胞形成的丝状结构比对照细胞长约10倍。荧光标记后，在亚MIC处理的细胞中细胞隔膜没有形成，但DNA正在分裂。锐劲特对C.艰难梭菌，显着减少毒素的生产和减弱炎症反应。利地尼唑还引起显著的细胞分裂效应，表明潜在的作用机制。
Ridinilazole (SMT19969) is a narrow-spectrum, non-absorbable antimicrobial with activity against Clostridium difficile undergoing clinical trials. The purpose of this study was to assess the pharmacological activity of ridinilazole and assess the effects on cell morphology. Antibiotic killing curves were performed using the epidemic C. difficile ribotype 027 strain, R20291, using supra-MIC (4× and 40×) and sub-MIC (0.125×, 0.25× and 0.5×) concentrations of ridinilazole. Following exposure, C. difficile cells were collected for cfu counts, toxin A and B production, and morphological changes using scanning electron and fluorescence microscopy. Human intestinal cells (Caco-2) were co-incubated with ridinilazole-treated C. difficile growth medium to determine the effects on host inflammatory response (IL-8). Treatment at supra-MIC concentrations (4× and 40× MIC) of ridinilazole resulted in a significant reduction in vegetative cells over 72 h (4 log difference, P < 0.01) compared with controls without inducing spore formation. These results correlated with a 75% decrease in toxin A production (P < 0.05) and a 96% decrease in toxin B production (P < 0.05). At sub-MIC levels (0.5× MIC), toxin A production was reduced by 91% (P < 0.01) and toxin B production was reduced by 100% (P < 0.001), which resulted in a 74% reduction in IL-8 release compared with controls (P < 0.05). Sub-MIC (0.5×)-treated cells formed filamentous structures ∼10-fold longer than control cells. Following fluorescence labelling, the cell septum was not forming in sub-MIC-treated cells, yet the DNA was dividing. Ridinilazole had robust killing effects on C. difficile that significantly reduced toxin production and attenuated the inflammatory response. Ridinilazole also elicited significant cell division effects suggesting a potential mechanism of action.