Narrow-spectrum inhibitors targeting an alternative menaquinone biosynthetic pathway of Helicobacter pylori
Narrow-spectrum inhibitors targeting an alternative menaquinone biosynthetic pathway of Helicobacter pylori
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DOI：
10.1016/j.jiac.2016.05.012
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发表时间：
2016-09-01
影响因子：
2.2
通讯作者：
Nakano, Hirofumi
中科院分区：
文献类型：
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作者：
Yamamoto, Tsuyoshi;Matsui, Hidenori;Nakano, Hirofumi
我们的目的是确定窄谱的天然化合物，特异性地抑制甲萘醌（MK;维生素K2）的替代生物合成途径（富他洛新途径）的幽门螺杆菌。采用纸片法检测了6183种微生物的培养液样品，其中使用了以下3种指示微生物中的2种的不同组合：耐盐芽孢杆菌C-125和刚毛北里孢KM-6054（T），它们仅具有MK生物合成的富他核苷途径，以及枯草芽孢杆菌H17，其仅具有典型的MIC生物合成途径。从培养液样品中分离的大多数活性化合物来自多不饱和脂肪酸（PUFA）家族。从链霉菌K12-1112的培养液中仅分离出一种化合物，siamycin I（一种21-残基套索肽抗生素），靶向了futalosine途径。比较了代表性多不饱和脂肪酸和siamycin I对B. halodurans或K.通过补充MK废除刚毛。此后，H. pylori菌株SS 1和TN 2GF 4在肉汤培养物中被二十碳五烯酸（EPA）、二十二碳六烯酸（DHA）或siamycin I剂量依赖性地抑制，并且这些抑制作用被补充MK降低。在饮用水中每天给予EPA（100 μ M）、DHA（100 μ M）或siamycin I（2.5 μ M）可降低H。C57 BL/6小鼠胃粘膜中的pylori SS 1定植率分别降低了96%、78%和68%。这些数据表明，EPA，DHA，和siamycin I防止H。pylori感染，通过抑制MK生物合成的futalosine途径。2016年日本化疗学会和日本传染病协会。由爱思唯尔有限公司发布。保留所有权利。
We aimed to identify narrow-spectrum natural compounds that specifically inhibit an alternative menaquinone (MK; vitamin K2) biosynthetic pathway (the futalosine pathway) of Helicobacter pylori. Culture broth samples of 6183 microbes were examined using the paper disc method with different combinations of 2 of the following 3 indicator microorganisms: Bacillus halodurans C-125 and Kitasatospora setae KM-6054(T), which have only the futalosine pathway of MK biosynthesis, and Bacillus subtilis H17, which has only the canonical MIC biosynthetic pathway. Most of the active compounds isolated from culture broth samples were from the families of polyunsaturated fatty acids (PUFAs). Only one compound isolated from the culture broth of Streptomyces sp. K12-1112, siamycin I (a 21-residue lasso peptide antibiotic), targeted the futalosine pathway. The inhibitory activities of representative PUFAs and siamycin I against the growth of B. halodurans or K. setae were abrogated by supplementation with MK. Thereafter, the growth of H. pylori strains SS1 and TN2GF4 in broth cultures was dose-dependently suppressed by eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or siamycin I, and these inhibitory effects were reduced by supplementation with MK. Daily administration of EPA (100 mu M), DHA (100 mu M), or siamycin I (2.5 mu M) in drinking water reduced the H. pylori SS1 colonization in the gastric mucosa of C57BL/6 mice by 96%, 78%, and 68%, respectively. These data suggest that EPA, DHA, and siamycin I prevented H. pylori infection by inhibiting the futalosine pathway of MK biosynthesis. 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.