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; 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）：“分枝杆菌菌磷酸酯的毒力因子的生物合成。专有性分枝杆菌病原体和机会性分枝杆菌病原体在结核分枝杆菌复杂或以外（即非核核切片性mycobacteria and Mortation and tosbiatia and nortife and Tene n torewiese）[n Tormitia and torefiele and tormistia [n Tormistia] [n tormistia] [n tormistia and n t t torm]分枝杆菌感染的复杂性是由于独特的分枝杆菌感染的渗透性障碍所提供的许多抗生素的韧性，这也越来越难以治疗。麻风大麻菌的多种抗菌菌株威胁着麻风病的未来，NTM的感染正在上升，而在美国，耐药的NTM越来越多，并且在国外的发展是富含治疗方法的发展。据此，用于毒力所需的（Glyco）脂质的生物合成所需的分枝菌酶，参与细胞壁通透性屏障的强化是探索探索创新辅助药物的开发以添加到多余的辅助药物中，以改善临床临床胜诉。分枝杆菌Dimycocerosate酯（DIMS）是一组免费的脂质和糖脂（分别称为PDIMS和PGLS），是许多致病性分枝杆菌的外膜所特有的（例如昏暗的是主要的毒力因素，它会下调和颠覆免疫机制，增强细胞壁渗透性屏障，降低药物敏感性，并可能对宿主的巨噬细胞中的氧化防御提供了一层保护。拟议的项目将利用遗传和生化方法来提供有关DIM的生物合成的新机械知识。该项目将通过以四个亚目标为重点的目标来追求，并使用机会性病原体M. Marinum作为昏暗生产者的代表。 M. Marinum是结核分枝杆菌复合物的最接近的遗传亲戚，通常用于模拟结核分枝杆菌复杂发病机理的各个方面，并提供了比其他昏暗生产者更大的实验性障碍。解剖昏暗的生物合成将为探索创新辅助药物的发展的长期目标铺平道路，从而阻止昏暗的合成，从而有可能增强宿主防御能力，并（超级）对一些降低的分枝杆菌对某些抗菌药物治疗的敏感性。