Department of Molecular Pathology, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan.
Department of 2nd Internal Medicine, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan.
Proc Natl Acad Sci U S A. 2021 Apr 20;118(16). doi: 10.1073/pnas.2016469118.
, a pathogen responsible for gastric cancer, contains a unique glycolipid, cholesteryl-α-D-glucopyranoside (CGL), in its cell wall. Moreover, -glycans having α1,4-linked -acetylglucosamine residues (αGlcNAc) are secreted from gland mucous cells of gastric mucosa. Previously, we demonstrated that CGL is critical for survival and that αGlcNAc serves as antibiotic against by inhibiting CGL biosynthesis. In this study, we tested whether a cholesterol analog, cholest-4-en 3-one (cholestenone), exhibits antibacterial activity against in vitro and in vivo. When the standard strain ATCC 43504 was cultured in the presence of cholestenone, microbial growth was significantly suppressed dose-dependently relative to microbes cultured with cholesterol, and cholestenone inhibitory effects were not altered by the presence of cholesterol. Morphologically, cholestenone-treated exhibited coccoid forms. We obtained comparable results when we examined the clarithromycin-resistant strain "2460." We also show that biosynthesis of CGL and its derivatives cholesteryl-6--tetradecanoyl-α-D-glucopyranoside and cholesteryl-6--phosphatidyl-α-D-glucopyranoside in is remarkably inhibited in cultures containing cholestenone. Lastly, we asked whether orally administered cholestenone eradicated strain SS1 in C57BL/6 mice. Strikingly, mice fed a cholestenone-containing diet showed significant eradication of from the gastric mucosa compared with mice fed a control diet. These results overall strongly suggest that cholestenone could serve as an oral medicine to treat patients infected with , including antimicrobial-resistant strains.
幽门螺杆菌，一种导致胃癌的病原体，其细胞壁含有一种独特的糖脂，即胆固醇-α-D-吡喃葡萄糖苷（CGL）。此外，胃黏膜腺黏液细胞会分泌带有α1,4-连接的乙酰氨基葡萄糖残基（αGlcNAc）的-β-聚糖。先前，我们已经证实 CGL 对于 的生存至关重要，并且 αGlcNAc 可通过抑制 CGL 生物合成而充当针对 的抗生素。在这项研究中，我们测试了胆固醇类似物胆甾-4-烯-3-酮（胆甾酮）是否在体外和体内对 具有抗菌活性。当标准菌株 ATCC 43504 在胆甾酮存在下培养时，与用胆固醇培养的微生物相比，微生物生长受到显著的剂量依赖性抑制，并且胆固醇的存在并不改变胆甾酮的抑制作用。形态上，胆甾酮处理过的 表现出球菌形态。当我们检查克拉霉素耐药菌株“2460”时，我们获得了类似的结果。我们还表明，CGL 及其衍生物胆甾醇-6--十四烷酰基-α-D-吡喃葡萄糖苷和胆甾醇-6--磷酸-α-D-吡喃葡萄糖苷的生物合成在含有胆甾酮的培养物中显著受到抑制。最后，我们询问了口服胆甾酮是否可以根除 SS1 菌株在 C57BL/6 小鼠中的感染。令人惊讶的是，与喂食对照饮食的小鼠相比，喂食含胆甾酮饮食的小鼠胃黏膜中 的根除率显著提高。总的来说，这些结果强烈表明胆甾酮可以作为一种口服药物来治疗感染 的患者，包括对抗生素耐药菌株的治疗。
