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：
7559619
负责人：
LUIS E QUADRI
金额：
$ 31.34万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7559619
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）是结核病（TB）的病原体，是一种危害严重的病原体。对全球公共卫生的影响和生物恐怖主义的潜在媒介。 Mt 通过空气飞沫传播吸入 1-10 个细菌就足以产生感染，从而导致症状性疾病。这疾病控制中心已将多重耐药 (MDR) Mt 纳入生物制剂 C 类用于针对生物恐怖主义的公共卫生准备。耐多药结核病被认为是一种新出现的传染病。无法治疗的耐多药结核病的死亡率为 40-60%。耐多药结核病爆发的威胁对所有现有药物都具有抵抗力自然出现或生物恐怖主义产生的抗结核药物是一个令人震惊的情况。公共卫生防备耐多药结核病需要针对传统和耐药性开发新的化疗方法非常规 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质和糖脂是替代药物的目标，单独或联合治疗将有助于预防和治疗耐多药结核病。此类药物会在爆发不可阻挡的结核分枝杆菌感染时，这是一条重要的生物防御线所有常规可用的抗生素。阐明这些 Mt 脂质/糖脂的生物合成是一个重要的课题加速此类药物开发的重要一步。最近的研究表明，一组细胞包膜定位的 Mt 脂质（称为 PDIM）是动物感染中完全毒力所必需的模型。最近证明 PDIM 相关糖脂（称为 PGL）的生产导致小鼠模型中 Mt 高毒力表型。其他研究表明 PGL 和 PDIM 参与对抗宿主免疫机制的途径。这些事实表明，PDIM PGLs（统称为DPKs）在结核病发病机制中发挥着重要作用。拟议的研究将调查 DPK 合成中的几个假设步骤，并探索第一个 PGL合成抑制剂。获得的知识将为 DPK 合成提供重要的见解并揭示开发 DPK 合成抑制剂的途径，这些抑制剂将作为有价值的先导化合物开发新型抗结核药物和工具来破译 DPK 在感染特定阶段的相关性因为它们可用于暂时控制动物模型中的 DPK 合成。