Mycobacterial PDIM/PGL: synthesis pathway and inhibition

分枝杆菌 PDIM/PGL：合成途径和抑制

基本信息

批准号：
7756601
负责人：
LUIS E QUADRI
金额：
$ 33.31万
依托单位：
BROOKLYN 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：
2006-02-15 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7756601
关键词：
Abbreviations Acyl Carrier Protein Acyltransferase Amino Acids Anabolism Animal Model Animals Antibiotics Antitubercular Agents Atmospheric Pressure Bacteria Biological Products Bioterrorism Breathing Carrier Proteins Categories Centers for Disease Control and Prevention (U.S.)Chloramphenicol O-Acetyltransferase Coenzyme A Colorado Combined Modality Therapy Complement component C1s Computer Simulation Development Devices Disease Disease Outbreaks Drug Resistant Tuberculosis Emerging Communicable Diseases Enzymes Esterification Event Fatty Acids Figs - dietary Genus Mycobacterium Glycolipids Glycols Growth Homologous Gene Hydroxybenzoic Acids Hydroxyl Radical Immune In Vitro Individual Infection Institutes Knowledge Lead Letters Ligase Lipids Marrow Mass Spectrum Analysis Methylation Modeling Molecular Models Mono-S Multi-Drug Resistance Mutagenesis Mycobacterium tuberculosis Octanols Organic Synthesis Oxidoreductase Palmitoyl Coenzyme A Pathogenesis Pathway interactions Pharmaceutical Preparations Phenotype Play Production Prophylactic treatment Proteins Public Health Radiolabeled Reaction Readiness Research Personnel Resistance Role Sequence Analysis Soil Staging Tertiary Protein Structure Thin Layer Chromatography Tuberculosis Universities Virulence Work analog base biodefense cell envelope chemical genetics chemotherapy chorismate pyruvate lyase college in vitro activity inhibitor/antagonist insight killings macrophage medical schools molecular modeling mortality mouse model mycobacterial mycocerosic acid novel pathogen petroleum ether polyketide synthase radiotracer tool tuberculosis drugs

项目摘要

Mycobacterium tuberculosis (Mt),the etiologic agent of tuberculosis (TB),is a pathogen with a serious impact on global public health and a potential agent for bioterrorism. Mt spreads by airborne droplets and inhalation of 1-10bacteria is sufficient to produce an infection that can result in symptomatic disease. The Center for Disease Control has included multiple-drug resistant (MDR) Mt in Category C of biological agents for public health preparedness against bioterrorism. MDR TB is considered an emerging infectious disease.. The mortality rate of untreatable MDR TB is 40-60%. The threat of MDR TB outbreaks resistant to all current anti-TB drugs, resulting either from natural emergence or bioterrorism, is an alarming scenario. Public health preparedness against MDR TB requires development of new chemotherapies against conventional and unconventional Mt targets to kill the bacterium or impair its virulence or growth in the host. Mt enzymes needed for synthesis of lipids and glycolipids required for virulence are targets for alternative drugs, which alone or in combination therapies, will be useful in prophylaxisand treatment of MDR TB. Such drugs will represent an important line of biodefense in the event of outbreaks of unstoppable Mt infections resistant to all conventional available antibiotics. Elucidation of the biosynthesis of these Mt lipids/glycolipids is an important step towards accelerating development of such drugs. Recent studies revealed that a group of cell-envelope-localized Mt lipids (referred to as PDIMs) is required for full virulence in animal infection models. Production of PDIM-related glycolipids (referred to as PGLs) was recently demonstrated to be responsible for Mt hypervirulent phenotype in a mouse model. Additional studies indicate that PGLs and PDIMs are involved in pathways that counteract host immune mechanisms. These facts suggest that PDIMs and PGLs (collectively referred to as DPKs) play an important role in TB pathogenesis. The proposed studies will investigated several hypothesized steps in DPK synthesis and explore the development of a first PGL synthesis inhibitor. The knowledge gained will provide important insight into DPK synthesis and reveal avenues for development of DPK synthesis inhibitors that will serve as valuable lead compounds in the development of novel anti-TB drugs and tools to decipher the relevance of DPK at specific stages of infection since they could be used to temporally control DPK synthesis in animal models.

结核分枝杆菌（MT），结核病的病因（TB）是一种严重的病原体对全球公共卫生的影响和生物恐怖主义的潜在药物。山通过空中液滴蔓延，吸入1-10bacteria足以产生可能导致有症状疾病的感染。这疾病控制中心包括在生物学剂C类中耐药（MDR）MT 为反对生物恐怖主义的公共卫生准备。 MDR TB被认为是一种新兴的传染病。不可治疗的MDR TB的死亡率为40-60％。 MDR TB暴发的威胁对所有当前由于自然出现或生物恐怖主义导致的抗TB药物是一种令人震惊的情况。公共卫生针对MDR TB的准备性需要开发针对常规和的新化学疗法非常规的MT靶标可杀死细菌或损害其宿主中其毒力或生长。 MT酶毒力所需的脂质和糖脂的合成所需的是替代药物的靶标，单独或联合疗法中，将有助于预防和MDR TB的治疗。这样的药物会在发生不可阻挡的MT感染的情况下，代表了重要的生物形式线所有常规的可用抗生素。阐明这些MT脂质/糖脂的生物合成是一种加速此类药物开发的重要步骤。最近的研究表明，一组细胞 - 含有定位的MT脂质（称为PDIMS）是动物感染中完全毒力的型号。最近证明，与PDIM相关的糖脂生产（称为PGLS）是负责小鼠模型中MT高毒性表型。其他研究表明PGL和 PDIM参与抵消宿主免疫机制的途径。这些事实表明pdims PGL（共同称为DPK）在结核病发病机理中起重要作用。提议研究将研究DPK合成中的几个假设的步骤，并探索第一个的发展 PGL合成抑制剂。获得的知识将为DPK综合提供重要的见解并揭示开发DPK合成抑制剂的途径，这些抑制剂将作为宝贵的铅化合物开发新型的抗TB药物和工具，以破译DPK在特定阶段的感染阶段的相关性由于它们可用于在动物模型中暂时控制DPK合成。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cooperation between a coenzyme A-independent stand-alone initiation module and an iterative type I polyketide synthase during synthesis of mycobacterial phenolic glycolipids.

DOI：
10.1021/ja904792q
发表时间：
2009-11-25
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
He, Weiguo;Soll, Clifford E.;Chavadi, Sivagami Sundaram;Zhang, Guangtao;Warren, J. David;Quadri, Luis E. N.
通讯作者：
Quadri, Luis E. N.