Targeting FtsZ for antibiotics discovery

重点开发耐药病原菌新药，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）。进行了以下两个次级项目。从海洋微生物培养物中筛选抑制结核分枝杆菌中FtsZ作用的提取物：细菌微管蛋白同源物FtsZ是一种必需的细胞分裂蛋白，它以gtp依赖的方式聚合，在隔膜部位形成一个细胞动力学环，称为Z环。由于FtsZ的失活或FtsZ组装的改变会抑制Z环和隔膜的形成，因此FtsZ是开发新型抗菌药物的一个有希望的靶点。我们从海洋微生物采集的提取液中筛选了15000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离，用反ph…More酶高效液相色谱纯化。用核磁共振法测定了纯化样品的结构。最后，我们确定了一种对耐多药结核病具有强杀菌活性的新化合物。传统中药提取物对耐药病原菌的筛选：许多传统中药酊剂被认为具有杀菌活性。筛选了100种中药酊剂对MRSA、VRE和MDR-TB细菌生长的抑制作用。选取活性最强的酊剂，采用溶剂分割粗分馏，硅胶层析和薄层色谱纯化。两种高活性化合物是酰化间苯三酚和三酮的类似物。因此，我们合成了一系列酰化间苯三酚和三酮，并测试了它们对MRSA、VRE和耐多药结核病的活性。具有C12侧链的四甲基化三酮是最有效的化合物（对MRSA的MIC约为1.0 μg/ml），并且被证明可以刺激静息细胞悬液的氧气消耗，这表明主要目标是细胞质膜。少

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