Studies on the Biological Mechanisms of Antibiotics

抗生素的生物学机制研究

• 批准号: 9249067
• 负责人: Daniel Kahne
• 金额: $ 56.13万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249067
• 关键词: Actinomyces Infections; Active Sites; Affinity; Anabolism; Animals; Antibiotic Resistance; Antibiotics; Bacteria; Bacterial Antibiotic Resistance; Bacterial Infections; Bambermycins; Binding; Biochemical; Biological; Biological Assay; Carbohydrates; Cell Wall; Cell membrane; Cells; Cellular Assay; Chemistry; Clinical; Crystallization; Cytolysis; Ensure; Enzyme Inhibition; Enzymes; Family; Genes; Glycolipids; Glycopeptide Antibiotics; Glycopeptides; Gram-Negative Bacteria; Health; Human; In Vitro; Infection; Kinetics; Lead; Libraries; Lipids; Measures; Methods; Molecular; Molecular Bank; Monobactams; Mutation; Natural Products; Nature; Organic Chemistry; Organism; Osmotic Pressure; Pathway interactions; Peptidoglycan; Peptidoglycan glycosyltransferase; Pharmaceutical Preparations; Play; Polymers; Polysaccharides; Predisposition; Process; Reporting; Research; Resistance; Role; Series; Staphylococcus aureus; Structure; Surface; United States National Institutes of Health; Work; analog; bacterial genetics; base; beta-Lactams; cellular targeting; crosslink; density; design; high throughput screening; improved; in vitro Assay; inhibitor/antagonist; lead series; novel; polymerization; pre-clinical; prevent; process optimization; programs; public health relevance; resistance frequency; resistance mechanism; screening

 DESCRIPTION (provided by applicant): Antibiotic resistant bacterial infections pose a serious threat to human health. Resistance is increasing while research into new antibiotics and possible new targets is lagging. Both Gram-positive and Gram-negative bacteria are surrounded by a cross-linked carbohydrate polymer, peptidoglycan (PG). This polymer is essential for bacterial survival because it stabilizes the cell membrane against high internal osmotic pressures. Peptidoglycan biosynthesis is a major target for antibiotics because interfering with this process leads to cell lysis. Indeed, the beta-lactams and glycopeptide antibiotics inhibit PG biosynthesis. Many PG biosynthetic enzymes are already targeted by clinically used antibiotics; however, one class of especially promising targets, the peptidoglycan glycosyltransferases (PGTs), remains unexploited. This research program is focused on discovering inhibitors of PGTs. These enzymes are attractive targets because their functions are essential, their structures are highly conserved in all bacteria, they have no mammalian homologs and they are located on the outer surface of the plasma membrane, which makes them more accessible to inhibitors than intracellular enzymes. The research described here constitutes an integrated, comprehensive program to discover and develop PGT inhibitors using library screening, synthetic organic chemistry, biochemical and cellular assays, structural studies, and bacterial genetics. The proposed work may lead to new compounds to treat antibiotic-resistant infections.

 描述（由申请人提供）：抗生素耐药细菌感染对人类健康构成严重威胁。耐药性正在增加，而对新抗生素和可能的新靶点的研究却滞后。革兰氏阳性和革兰氏阴性细菌都被交联的碳水化合物聚合物肽聚糖（PG）包围。这种聚合物对于细菌的生存是必不可少的，因为它可以稳定细胞膜以抵抗高的内部渗透压。肽聚糖生物合成是抗生素的主要靶标，因为干扰该过程会导致细胞裂解。实际上，β-内酰胺类和糖肽类抗生素抑制PG生物合成。许多PG生物合成酶已经被临床使用的抗生素靶向;然而，一类特别有前途的靶点，肽聚糖糖基转移酶（PGTs），仍然未被开发。这项研究计划的重点是发现PGTs的抑制剂。这些酶是有吸引力的靶标，因为它们的功能是必需的，它们的结构在所有细菌中高度保守，它们没有哺乳动物同源物，并且它们位于质膜的外表面上，这使得它们比细胞内酶更容易被抑制剂接近。这里描述的研究构成了一个综合的，全面的计划，发现和开发PGT抑制剂使用库筛选，合成有机化学，生物化学和细胞测定，结构研究和细菌遗传学。这项工作可能会导致新的化合物来治疗耐药性感染。