BIOSYNTHESIS OF MYCOBACTERIAL DIMYCOCEROSATE ESTER VIRULENCE FACTORS

分枝杆菌二霉菌蜡酸酯毒力因子的生物合成

• 批准号: 8626584
• 负责人: LUIS E QUADRI
• 金额: $ 43.07万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8626584
• 关键词: Abbreviations; Acids; Acyl Carrier Protein; Acyltransferase; Adjuvant; Anabolism; Anti-Infective Agents; Antibiotic Resistance; Antibiotics; Bacteria; Biochemical; Boxing; Carrier Proteins; Cell Wall; Cells; Cities; Clinical; Complex; Core Facility; Coupled; Data; Development; Drug Targeting; Drug resistance; Enzymes; Esters; Extreme drug resistant tuberculosis; Foundations; Future; Genetic; Genus Mycobacterium; Glycolipids; Goals; Host Defense; Hydroxybenzoic Acids; Immune; In Vitro; Infection; Knowledge; Laboratories; Leprosy; Letters; Ligase; Light; Lipids; Liquid Chromatography; Mass Spectrum Analysis; Membrane; Modeling; Morbidity - disease rate; Multi-Drug Resistance; Mycobacterium Infections; Mycobacterium tuberculosis; New York; Outcome; Pathogenesis; Permeability; Pharmaceutical Preparations; Predisposition; Production; Relative (related person); Rest; Site; Subway; Synthesis Chemistry; System; Therapeutic; Thin Layer Chromatography; Universities; Virulence; Virulence Factors; adenylate; antimicrobial drug; base; college; empowered; experience; fortification; improved; inhibitor/antagonist; innovation; macrophage; medical schools; mortality; mycobacterial; non-tuberculosis mycobacteria; pathogen; polyketide synthase; public health relevance; resilience; resistant strain

DESCRIPTION (provided by applicant): "BIOSYNTHESIS OF MYCOBACTERIAL IMYCOCEROSATE ESTER VIRULENCE FACTORS. Obligate mycobacterial pathogens and opportunistic mycobacterial pathogens within the Mycobacterium tuberculosis complex or outside of this complex (i.e., non-tuberculosis mycobacteria [NTM]) are responsible for substantial morbidity and mortality worldwide. Treatment of mycobacterial infections is complicated by the resilience of mycobacteria to many antibiotics afforded by the permeability barrier of the unique mycobacterial cell wall. Mycobacterial infections are becoming increasingly difficult to treat due to the rise of acquired drug resistance as well. Multidrug-resistant and extensively drug-resistant strains of M. tuberculosis pose a global menace. Multidrug-resistant strains of M. leprae threaten to compromise the future of leprosy control. Infections of NTM are on the rise, and drug resistant NTM are a growing concern in the USA and abroad. Development of the rich therapeutic arsenal needed to counter the rise of drug resistant mycobacteria requires exploitation of conventional and unconventional drug targets and therapeutic approaches. In this light, the mycobacterial enzymes needed for the biosynthesis of (glyco)lipids required for virulence and involved in the fortification of the cell wall permeabilit barrier are target candidates for exploring the development of innovative adjuvant drugs to be added to multidrug treatments to improve clinical outcomes. Mycobacterial dimycocerosate esters (DIMs) are a group of free lipids and glycolipids (hereinafter referred to as PDIMs and PGLs, respectively) unique to the outer membrane of many pathogenic mycobacteria (e.g., M. tuberculosis complex, M. leprae and several NTM). DIMs are major virulence factors that down-regulate and subvert immune mechanisms, strengthen the cell wall permeability barrier, reduce drug susceptibility and, possibly, afford a layer of protection against the oxidative defense in th macrophage of the host. The proposed project will utilize genetic and biochemical approaches to deliver new mechanistic knowledge on the biosynthesis of DIMs. The project will be pursued via a focused aim with four sub aims and using the opportunistic pathogen M. marinum as a representative of DIM producers. M. marinum, the closest genetic relative of the M. tuberculosis complex, is often utilized to model aspects of M. tuberculosis complex pathogenesis and offers greater experimental tractability than other DIM producers. Dissecting DIM biosynthesis will pave the way to the long-term goal of exploring the development of innovative adjuvant drugs that block DIM synthesis, thus having the potential to empower host defenses and (hyper)sensitizing DIM-producing mycobacteria to some antimicrobial drug treatments.

描述（由申请人提供）：“分枝杆菌真菌蜡酯毒力因子的生物合成。结核分枝杆菌复合体内或该复合体外（即非结核分枝杆菌 [NTM]）的专性分枝杆菌病原体和机会性分枝杆菌病原体（即非结核分枝杆菌 [NTM]）是导致大量发病和发生的原因。全世界分枝杆菌感染的治疗很复杂。由于分枝杆菌独特的细胞壁的渗透性屏障对许多抗生素具有抵抗力，由于获得性耐药和广泛耐药菌株的增加，分枝杆菌感染变得越来越难以治疗。结核病构成了全球性的威胁，对麻风病控制的未来构成了威胁。开发丰富的治疗手段来应对耐药分枝杆菌的增加需要开发传统和非常规的药物靶点和治疗方法。有鉴于此，毒力所需的（糖）脂质生物合成所需的分枝杆菌酶并参与细胞壁通透性屏障的强化，是探索开发创新辅助药物的目标候选药物，将其添加到多药治疗中以改善临床结果。分枝杆菌二霉菌蜡酸酯（DIM）是许多致病分枝杆菌（例如结核分枝杆菌复合体、麻风分枝杆菌和几种 NTM）外膜所特有的一组游离脂质和糖脂（以下分别称为 PDIM 和 PGL）。 DIM 是主要的毒力因子，可下调和颠覆免疫机制、增强细胞壁通透性屏障、降低药物敏感性，并可能为宿主巨噬细胞的氧化防御提供一层保护。拟议的项目将利用遗传和生化方法来提供有关 DIM 生物合成的新机械知识。该项目将通过一个有四个子目标的重点目标来实现，并使用机会性病原体 M. marinum 作为 DIM 生产者的代表。 M. marinum 是结核分枝杆菌复合体的最接近的遗传亲属，通常用于模拟结核分枝杆菌复合体发病机制的各个方面，并且比其他 DIM 生产者提供更好的实验易处理性。剖析 DIM 生物合成将为探索开发阻断 DIM 合成的创新辅助药物的长期目标铺平道路，从而有可能增强宿主防御并使产生 DIM 的分枝杆菌对某些抗菌药物治疗（超）敏感。

项目成果

Mycobacteria Encode Active and Inactive Classes of TesB Fatty-Acyl CoA Thioesterases Revealed through Structural and Functional Analysis.

• DOI: 10.1021/acs.biochem.6b01049
• 发表时间: 2017-03
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: C. Swarbrick;Glennon V Bythrow;D. Aragão;Gabrielle A Germain;L. Quadri;J. Forwood