Department of Integrative Biomedical and Diagnostic Sciences, Oregon Health and Science University, Portland, Oregon 97239, United States.
J Med Chem. 2023 Jun 22;66(12):7909-7925. doi: 10.1021/acs.jmedchem.3c00272. Epub 2023 Jun 7.
We designed and synthesized analogues of a previously identified biofilm inhibitor to improve solubility, retain inhibitory activities, and to facilitate encapsulation into pH-responsive hydrogel microparticles. The optimized lead compound showed improved solubility of 120.09 μg/mL, inhibited biofilm with an IC value of 6.42 μM, and did not affect the growth of oral commensal species up to a 15-fold higher concentration. The cocrystal structure of with GtfB catalytic domain determined at 2.35 Å resolution revealed its active site interactions. The ability of to inhibit Gtfs and to reduce glucan production has been demonstrated. The hydrogel-encapsulated biofilm inhibitor (), generated by encapsulating in hydrogel, selectively inhibited biofilms like . Treatment of -infected rats with or resulted in a significant reduction in buccal, sulcal, and proximal dental caries compared to untreated, infected rats.
我们设计并合成了先前鉴定的生物膜抑制剂类似物，以提高其溶解度、保持抑制活性，并便于封装到 pH 响应水凝胶微球中。优化的先导化合物[化合物名称]显示出 120.09μg/mL 的改善溶解度，IC 值为 6.42μM 抑制生物膜，并且在高达 15 倍更高浓度下不影响口腔共生种的生长。在 2.35Å分辨率下确定的与 GtfB 催化结构域的共晶结构揭示了其活性位点相互作用。已经证明[化合物名称]能够抑制 Gtfs 和减少葡聚糖的产生。通过将[化合物名称]封装在水凝胶中生成的水凝胶包封的生物膜抑制剂()，选择性地抑制了生物膜，类似于。用[化合物名称]或[]治疗感染的大鼠，与未治疗的感染大鼠相比，颊、沟和近牙龋齿明显减少。
