Mycobacterial PDIM/PGL: synthesis pathway and inhibition

描述(申请人提供)：结核分枝杆菌(Mt)，结核病(TB)的病原体，是一种严重影响全球公共健康的病原体，也是潜在的生物恐怖主义因素。MT通过空气飞沫传播和吸入1-10个细菌足以产生可导致症状性疾病的感染。疾病控制中心已将多药耐药(MDR)结核列入C类生物制剂，用于公共卫生防范生物恐怖主义。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%。耐多药结核病暴发对当前所有抗结核药物产生抗药性，这一威胁是由自然出现或生物恐怖主义造成的，这是一个令人担忧的情况。针对耐多药结核病的公共卫生准备需要开发针对常规和非常规mt靶标的新化疗药物，以杀死细菌或削弱其毒力或在宿主中生长。合成毒力所需的脂类和糖脂所需的MT酶是替代药物的靶标，这些药物单独或联合治疗将在预防和治疗耐多药结核病方面有用。这些药物将代表着一条重要的生物防线，以防对所有常规可用抗生素产生抗药性的不可阻挡的mt感染爆发。阐明这些山梨醇/糖脂的生物合成是加速这类药物开发的重要一步。最近的研究表明，在动物感染模型中，一组细胞被膜定位的线粒体脂质(简称PDIMs)是完全毒力所必需的。最近证实，PDIM相关糖脂(简称PGL)的产生与小鼠模型中的mt超强毒力表型有关。更多的研究表明，PGLS和PDIMs参与了对抗宿主免疫机制的途径。这些事实表明，PDIMs和PGLS(统称为DPKs)在结核病的发病机制中发挥着重要作用。这项拟议的研究将研究DPK合成的几个假设步骤，并探索第一个PGL合成抑制剂的开发。所获得的知识将为DPK合成提供重要的洞察，并揭示DPK合成抑制剂的开发途径，这些DPK合成抑制剂将在开发新型抗结核药物和工具方面作为有价值的先导化合物，以破译DPK在特定感染阶段的相关性，因为它们可以用于在动物模型中暂时控制DPK的合成。

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.