Mycobacterial PDIM/PGL: synthesis pathway and inhibition

分枝杆菌 PDIM/PGL：合成途径和抑制

• 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
• 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

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)是一种严重危害人类健康的病原体，是结核病的病原体。 对全球公共卫生的影响和生物恐怖主义的潜在动因。MT通过空气中的液滴和 吸入1-100个细菌就足以产生可导致症状性疾病的感染。这个 疾病控制中心已将多药耐药(MDR)mt列入C类生物制剂 针对生物恐怖主义的公共卫生准备工作。耐多药结核病被认为是一种新出现的传染病。 无法治愈的耐多药结核病的死亡率为40%-60%。耐多药结核病暴发的威胁抵抗所有当前 由自然产生或生物恐怖主义产生的抗结核病药物是一个令人震惊的情景。公共卫生 预防耐多药结核病需要开发新的化疗药物来对抗传统和 非常规mt的目标是杀死细菌或削弱其毒力或在宿主中的生长。MT酶 合成毒力所需的脂类和糖脂是替代药物的靶标， 单独或联合治疗，将对耐多药结核病的预防和治疗有用。这样的药物会 代表了一条重要的生物防线，以防爆发无法阻止的耐甲氧西林金黄色葡萄球菌感染 所有常规的可用抗生素。对这些山梨醇/糖脂的生物合成的解释是 这是加快这类药物开发的重要一步。最近的研究表明，一群 在动物感染中，细胞膜定位的mt脂(称为pdims)是完全毒力所必需的。 模特们。PDIM相关糖脂(简称PGL)的生产最近被证明是 对小鼠模型中的mt超强毒力表型负责。更多的研究表明，PGLS和 PDIMs参与对抗宿主免疫机制的途径。这些事实表明，PDIM 而PGLS(统称为DPKs)在结核病的发病机制中起着重要作用。建议数 研究将调查合成DPK的几个假设步骤，并探索第一个步骤的发展 前列环素合成抑制剂。所获得的知识将为DPK的合成提供重要的见解并揭示 开发作为有价值的先导化合物的DPK合成抑制剂的途径 开发新的抗结核药物和工具以破译DPK在感染特定阶段的相关性 因为它们可以用来在动物模型中暂时控制DPK的合成。

项目成果

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.