Bacterial cell killing by topoisomerase I mediated DNA lesion

拓扑异构酶 I 介导的 DNA 损伤杀死细菌细胞

基本信息

批准号：
8186092
负责人：
Yuk-Ching Tse-Dinh
金额：
$ 40.25万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8186092
关键词：
Adverse effects Affinity Anti-Bacterial Agents Antibiotics Bacteria Bacterial DNA Topoisomerase I Bacterial Proteins Bacterial Typing Binding Biochemical Biochemical Genetics Biological Assay Candidate Disease Gene Cell Death Cells Cleaved cell Code Combined Modality Therapy Complex Computer Simulation Cultured Cells DNA DNA Binding DNA Topoisomerase IV DNA Topoisomerases DNA lesion Detection Development Docking Drug resistance Enzymes Escherichia coli Excision Family Funding Gel Genes Genetic Growth Human Inhibitory Concentration 50 Lead Lesion Malignant Neoplasms Measures Mediating Multi-Drug Resistance Mutation Pathway interactions Pharmaceutical Preparations Phosphotyrosine Poison Process Proteins Public Health Quinolones Recombinants Relaxation Research Activity Resistance Saccharomyces cerevisiae Screening procedure Site Speed Structure Structure-Activity Relationship Temperature Therapeutic Therapeutic Agents Topoisomerase Topoisomerase-I Inhibitor Toxic effect Type I DNA Topoisomerases Work Yeasts Yersinia pestis analog base cancer therapy cell killing combat counterscreen design endonuclease global health homologous recombination improved in vitro Assay inhibitor/antagonist mutant novel overexpression pathogen pharmacophore phosphoric diester hydrolase prevent recombinational repair repaired research study small molecule small molecule libraries success tool

项目摘要

DESCRIPTION (provided by applicant): This project targets bacterial type IA topoisomerase for discovery of novel antibacterial drugs as countermeasure for multi-drug resistant bacterial pathogens, including gram negatives. Drugs that initiate cell killing by trapping the covalent cleavage complex formed by type IB and type IIA topoisomerases are widely used in current anti-cancer and anti-bacterial therapy. Accumulation of type IA topoisomerase cleavage complex can trigger rapid bacterial cell death via the oxidative cell death pathway but specific inhibitors of type IA bacterial topoisomerase I that can be developed into new antibacterial drugs remain to be discovered. The proposed research activities for the next funding period would develop and utilize rapid cell based applicable for HTS assay format to identify small molecule compounds that have antibacterial activity due to specific interaction with bacterial topoisomerase I. Inhibitors of bacterial topoisomerase I identified from screening would be analyzed biochemically for mechanism of action and structure activity relationship. Priority would be given to compounds with low toxicity that are active against gram negative Escherichia coli and Yersinia pestis in order to identify leads that can be used in development of therapeutic agents against gram negative pathogens. Bacterial proteins that process trapped topoisomerase cleavage complexes will be identified with genetic and biochemical experiments. The repair proteins involved may be useful new targets for combination therapy with antibiotics targeting both type IA and type IIA topoisomerases. Success in these proposed experiments would provide tools and leads for development of novel antibacterial drugs for the urgent public health problem of bacterial pathogens resistant to all current antibiotics. PUBLIC HEALTH RELEVANCE: This project targets bacterial topoisomerase I enzyme for discovery of specific inhibitors. The proposed work would greatly aid the development of new antibacterial compounds against a novel target as part of the much needed arsenal to combat the global health problem of multi-drug drug resistant bacterial pathogens, including gram negatives.

描述（由申请人提供）：该项目以细菌 IA 型拓扑异构酶为目标，发现新型抗菌药物，作为多重耐药细菌病原体（包括革兰氏阴性菌）的对策。通过捕获 IB 型和 IIA 型拓扑异构酶形成的共价裂解复合物来启动细胞杀伤的药物广泛应用于当前的抗癌和抗菌治疗中。 IA型拓扑异构酶裂解复合物的积累可通过氧化细胞死亡途径引发细菌细胞快速死亡，但可开发成新抗菌药物的IA型细菌拓扑异构酶I的特异性抑制剂仍有待发现。下一个资助期的拟议研究活动将开发和利用适用于 HTS 测定格式的快速细胞来鉴定由于与细菌拓扑异构酶 I 的特异性相互作用而具有抗菌活性的小分子化合物。将从筛选中鉴定出的细菌拓扑异构酶 I 抑制剂进行分析生化作用机制和结构活性关系。将优先考虑对革兰氏阴性大肠杆菌和鼠疫耶尔森氏菌具有活性的低毒性化合物，以便确定可用于开发针对革兰氏阴性病原体的治疗剂的先导化合物。处理被捕获的拓扑异构酶裂解复合物的细菌蛋白将通过遗传和生化实验进行鉴定。所涉及的修复蛋白可能是针对 IA 型和 IIA 型拓扑异构酶的抗生素联合治疗的有用新靶点。这些拟议实验的成功将为开发新型抗菌药物提供工具和线索，以解决对所有现有抗生素产生耐药性的细菌病原体这一紧迫的公共卫生问题。公共健康相关性：该项目以细菌拓扑异构酶 I 为目标，以发现特定的抑制剂。拟议的工作将极大地帮助针对新靶点开发新的抗菌化合物，作为解决包括革兰氏阴性菌在内的多重耐药细菌病原体的全球健康问题急需的武器库的一部分。