Investigation of Mycobacterial GMC Oxidoreductase Rv3409c

分枝杆菌 GMC 氧化还原酶 Rv3409c 的研究

基本信息

批准号：
7770620
负责人：
NICOLE S SAMPSON
金额：
$ 23.16万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-27 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7770620
关键词：
Address Alcohols Antibiotics Antimycobacterial Agents Attenuated Biological Assay Biology Cells Cholesterol Oxidase Complex Crystallization Development Down-Regulation Drug resistance Enzymes Extreme drug resistant tuberculosis Flavins Genes Genome Genus Mycobacterium Glycolipids Goals Human Immune response Immunology Infection Investigation Kinetics Knowledge Laboratories Lipids Mass Spectrum Analysis Morphology Multi-Drug Resistance Multidrug-Resistant Tuberculosis Mutation Mycobacterium tuberculosis Mycobacterium tuberculosis H37Rv National Institute of Allergy and Infectious Disease Open Reading Frames Organism Oxidases Oxidoreductase Oxygen Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Phenotype Play Population Proteins Reaction Research Rifampin Role Streptomyces Structure Substrate Specificity Targeted Research Tuberculosis Virulence Virulent Work World Health Organization base chemotherapeutic agent cofactor combat drug discovery genome sequencing isoniazid mouse model mutant mycobacterial novel strategies pathogen public health relevance research study small molecule sugar tuberculosis drugs

项目摘要

DESCRIPTION (provided by applicant): The World Health Organization estimates that 2 million people die every year from tuberculosis and that 30% of the world's population is infected. Multi-drug resistant organisms are widespread and extensively drug resistant organisms are emerging. New approaches are required to combat these virulent and drug resistant organisms (MDR/XDR TB). The function of Rv3409c is unknown. It is distantly related to bacterial cholesterol oxidases and was annotated as a cholesterol oxidase during genome sequencing. Experiments with purified protein and transposon mutants revealed that Rv3409c is not a cholesterol oxidase. The mutant has a colony morphology phenotype and lipid profiling has identified lipids present in the mutant that are not present in wild-type mycobacteria. The proposed experiments are aimed at characterizing Rv3409c. The hypothesis is that Rv3409c is a glycolipid oxidase and that this activity represents a new target for anti-MDR-TB pharmaceutical development. The aim of this work is 1) to elucidate the structure of lipids unique or missing in the Rv3409c mutant and 2) to determine the kinetic activity and substrate specificity of the Rv3409c enzyme. PUBLIC HEALTH RELEVANCE: The proposed research fits within the targeted research needs of NIAID that seeks the development of new chemotherapeutic agents against MDR/XDR TB. These experiments will provide a basis for discovering the function of this enzyme that is not present in humans and guide development of new antibiotics that would be effective against all forms of TB including MDR/XDR TB.

描述（由申请人提供）：世界卫生组织估计，每年有 200 万人死于结核病，世界上 30% 的人口受到感染。多重耐药微生物广泛存在，并且广泛耐药微生物不断出现。需要新的方法来对抗这些剧毒和耐药微生物（耐多药/广泛耐药结核病）。 Rv3409c 的功能未知。它与细菌胆固醇氧化酶关系较远，在基因组测序过程中被注释为胆固醇氧化酶。使用纯化蛋白和转座子突变体进行的实验表明，Rv3409c 不是胆固醇氧化酶。该突变体具有菌落形态表型，并且脂质分析已鉴定出突变体中存在野生型分枝杆菌中不存在的脂质。所提出的实验旨在表征 Rv3409c。假设 Rv3409c 是一种糖脂氧化酶，这种活性代表了抗 MDR-TB 药物开发的新靶标。这项工作的目的是 1) 阐明 Rv3409c 突变体中独特或缺失的脂质结构，2) 确定 Rv3409c 酶的动力学活性和底物特异性。公共健康相关性：拟议的研究符合 NIAID 的目标研究需求，该需求旨在开发针对 MDR/XDR TB 的新型化疗药物。这些实验将为发现这种人类中不存在的酶的功能提供基础，并指导开发可有效对抗所有形式结核病（包括耐多药/广泛耐药结核病）的新抗生素。