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Targeting FtsZ for antibiotics discovery

以 FtsZ 为目标进行抗生素发现

基本信息

批准号：
17590409
负责人：
KIRIKAE Teruo
金额：
$ 2.37万
依托单位：
International Medical Center of Japan, Research Institute
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

We focused on the development of novel drugs against drug-resitant pathogens, including multidrug-resistant Mycobacterium tuberculosis (MDR-TB), methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). The following two subprojects were undertaken.Screening of extracts from a marine microbial culture collection for inhibition of FtsZ action in M. tuberculosis: A bacterial tubulin homologue, FtsZ, is an essential cell division protein that polymerizes in a GTP-dependent manner, forming a cytokinetic ring, designated as the Z ring, at the septum site. Since inactivation of FtsZ or alteration of FtsZ assembly results in the inhibition of Z ring and septum formation, FtsZ is a promising target for new antimicrobial drug development. We screened 15,000 samples from extracts from marine microbial collection for FtsZ inhibitor. Consequently, 30 hit samples were obtained. These samples were fractionated by ethyl acetate and purified by reversed-ph … More ase HPLC. The structure of the purified sample was determined by NMR. Finally, we determined a novel compound with a strong bactericidal activity against MDR-TB.Screening of traditional herbal extracts for drug-resistant pathogens: It is believed that many traditional herbal tinctures had bactericidal activities. One hundred herbal tinctures were screened for the inhibition of bacterial growth of MRSA, VRE, and MDR-TB. A selection of the most active tinctures was crudely fractionated by solvent partition and purified by silica gel chromatography and TLC. Two highly active compounds were analogoues of acylated phloroglucinols and triketones. Therefore, a series of acylated phloroglucinols and triketones was synthesized and tested for activity against MRSA, VRE, and MDR-TB. A tetra-methylated triketone with a C12 side chain was the most active compound (MIC of around 1.0 μg/ml against MRSA) and was shown to stimulate oxygen consumption by resting cell suspensions, suggesting that the primary target was the cytoplasmic membrane. Less

我们专注于开发针对耐药病原体的新药，包括耐多药结核分枝杆菌（MDR-TB），耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素屎肠球菌（VRE）。开展了以下两个分项目：筛选海洋微生物培养物的提取物，以抑制FtsZ在M.肺结核：细菌微管蛋白同源物FtsZ是一种必需的细胞分裂蛋白，其以GTP依赖性方式聚合，在隔膜位点形成细胞动力学环，称为Z环。由于FtsZ的失活或FtsZ组装的改变导致Z环和隔膜形成的抑制，因此FtsZ是新的抗微生物药物开发的有希望的靶标。我们从海洋微生物收集的提取物中筛选了15，000个样品用于FtsZ抑制剂。因此，获得了30个命中样本。这些样品用乙酸乙酯分级， ...更多信息高效液相色谱法通过NMR确定纯化样品的结构。最后，我们确定了一种新的化合物具有很强的杀菌活性对耐多药结核病。筛选传统的草药提取物的耐药病原体：据信，许多传统的草药酊剂有杀菌活性。对一百种草药酊剂进行了筛选，以抑制耐甲氧西林金黄色葡萄球菌（MRSA）、耐甲氧西林金黄色葡萄球菌（VRE）和耐多药结核病（MDR-TB）细菌生长。通过溶剂分配法对活性最强的酊剂进行粗分馏，并通过硅胶色谱法和薄层色谱法进行纯化。两个高活性化合物是酰化间苯三酚和三酮的类似物。因此，合成了一系列酰化间苯三酚和三酮，并测试了其抗MRSA、VRE和MDR-TB的活性。具有C12侧链的四甲基化三酮是最具活性的化合物（对MRSA的MIC约为1.0 μg/ml），并显示通过静息细胞悬液刺激氧消耗，表明主要靶点是细胞质膜。少

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Survey of human immunodeficiency virus (HIV)-seropositive patients with mycobacterial infection in Japan.

日本人类免疫缺陷病毒（HIV）血清阳性分枝杆菌感染患者的调查。

DOI：
发表时间：
2005
期刊：
J Infect. 51(5)
影响因子：
0
作者：
Otsuka Y;Fujino T;Mori N;Sekiguchi J;Toyota E;Saruta K;Kikuchi Y;Sasaki Y;Ajisawa A;Otsuka Y;Nagai H;Takahara M;Saka H;Shirasaka T;Yamashita Y;Kiyosuke M;Koga H;Oka S;Kimura S;Mori T;Kuratsuji T;Kirikae T.
通讯作者：
Kirikae T.

Association of rpoB mutations with rifampicin resistance in Mycobacterium avium.

rpoB 突变与鸟分枝杆菌利福平耐药性的关联。