Mycobacterial PDIM/PGL: synthesis pathway and inhibition

分枝杆菌 PDIM/PGL：合成途径和抑制

• 批准号: 7174698
• 负责人: LUIS E QUADRI
• 金额: $ 31.67万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 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 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7174698
• 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; Disruption; Drug Resistant Tuberculosis; Drug resistance; Emerging Communicable Diseases; Enzymes; Esterification; Event; Fatty Acids; Figs - dietary; Genus Mycobacterium; Glycol; Glycolipids; Glycols; Growth; Homologous Gene; Hydroxybenzoic Acids; Hydroxyl Radical; Immune; In Vitro; Individual; Infection; Institutes; Knowledge; Lead; Letters; Ligase; Lipids; Localized; Marrow; Mass Spectrum Analysis; Medical; Methylation; Modeling; 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; Rate; 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; inhibitor/antagonist; insight; killings; macrophage; molecular modeling; mortality; mouse model; mycobacterial; mycocerosic acid; novel; pathogen; petroleum ether; polyketide synthase; radiotracer; tool; tuberculosis drugs

DESCRIPTION (provided by applicant): 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 1-10 bacteria 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 prophylaxis and 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.

描述（由申请人提供）：结核分枝杆菌（Mt）是结核病（TB）的病原体，是一种对全球公共卫生产生严重影响的病原体，也是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。美国疾病控制中心已将多重耐药 (MDR) Mt 纳入 C 类生物制剂，以应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%。由于自然出现或生物恐怖主义而导致对所有现有抗结核药物具有耐药性的耐多药结核病爆发的威胁令人震惊。针对耐多药结核病的公共卫生准备工作需要开发针对传统和非常规 Mt 靶标的新化疗方法，以杀死细菌或削弱其毒力或在宿主中的生长。合成毒力所需的脂质和糖脂所需的 Mt 酶是替代药物的目标，这些替代药物单独或联合治疗将有助于预防和治疗耐多药结核病。如果爆发对所有常规可用抗生素具有耐药性的不可阻挡的结核分枝杆菌感染，此类药物将成为重要的生物防御线。阐明这些 Mt 脂质/糖脂的生物合成是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）是动物感染模型中完全毒力所必需的。最近证明，PDIM 相关糖脂（称为 PGL）的产生是小鼠模型中 Mt 高毒力表型的原因。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 和 PGL（统称为 DPK）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 合成抑制剂的开发。所获得的知识将为 DPK 合成提供重要的见解，并揭示 DPK 合成抑制剂的开发途径，这些抑制剂将作为开发新型抗结核药物和工具的有价值的先导化合物，以破译 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。