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首页> 外文期刊>Drug Target Insights >Targeting Streptococcus pneumoniae UDP-glucose pyrophosphorylase (UGPase): in vitro validation of a putative inhibitor
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Targeting Streptococcus pneumoniae UDP-glucose pyrophosphorylase (UGPase): in vitro validation of a putative inhibitor

机译：靶向<斜体>链球菌肺炎料 - 肺炎 - 葡萄糖磷苷酶（UGPase）：对推定抑制剂的体外验证

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ABSTRACT Background: Genome plasticity of Streptococcus pneumoniae is responsible for the reduced efficacy of various antibiotics and capsular polysaccharide-based vaccines. Therefore, targets independent of capsular types are sought to control the pneumococcal pathogenicity. UDP-glucose pyrophosphorylase (UGPase) is one such desired candidate being responsible for the synthesis of UDP-glucose, a sugar precursor in capsular biosynthesis and metabolic Leloir pathway. Being crucial to pneumococcal pathobiology, the effect of UGPase inhibition on virulence was evaluated in vitro. Methods: A putative inhibitor, uridine diphosphate (UDP), was evaluated for effective inhibitory concentration in S. pneumoniae and A549 cells, its efficacy and toxicity. The effect of UDP on adherence and phagocytosis was measured in human respiratory epithelial (A549 and HEp-2) and macrophage (THP1 and J774.A.1) cell lines respectively. Results: A differential effective inhibitory concentration of UDP for UGPase inhibition was observed in S. pneumoniae and A549 cells, that is, 5 and 100 μM respectively. UDP treatments lowered percent cytotoxicity in pneumococcal-infected monolayers and didn’t exert adverse effects on viabilities. S. pneumoniae adherence to host cells decreased significantly with UDP treatments. UDP induced the secretion of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, and IL-8 and increased pneumococcal phagocytosis. Conclusion: Our study shows UDP-mediated decrease in the virulence of S. pneumoniae and demonstrates UDP as an effective inhibitor of pneumococcal UGPase.
机译：摘要背景：肺炎链球菌的基因组可塑性负责各种抗生素和荚膜多糖的疫苗的疗效降低。因此，寻求独立于囊型类型的目标来控制肺炎球菌致病性。 UDP-葡萄糖焦磷酸化酶（UGPase）是负责合成UDP-葡萄糖的这种期望的候选者，囊性生物合成和代谢Leloir途径的合成。对肺炎球菌病理学病症至关重要，在体外评价UGPase抑制对毒力的影响。方法：调用抑制剂，尿苷二磷酸（UDP），在肺炎肺炎和A549细胞中进行有效抑制浓度，其疗效和毒性。在人呼吸上皮（A549和HEP-2）和巨噬细胞（THP1和J74.A.1）细胞中，测量UDP对粘附和吞噬作用的影响。结果：在肺炎肺炎和A549细胞中观察到UGP酶抑制的UDP差异有效抑制浓度，即分别为5和100μm。 UDP治疗降低了肺炎球菌感染的单层中细胞毒性的百分比，对肺炎不利影响不利影响。肺炎肺炎对宿主细胞的粘附性显着降低了UDP治疗。 UDP诱导白细胞介素（IL）-1β，肿瘤坏死因子（TNF）-α，IL-6和IL-8的分泌以及肺炎球菌吞噬作用增加。结论：我们的研究表明，肺炎肺炎毒力的毒力的UDP介导的降低，并证明了UDP作为肺炎球菌UGPase的有效抑制剂。

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