BIOSYNTHESIS OF MYCOBACTERIAL DIMYCOCEROSATE ESTER VIRULENCE FACTORS

描述（由申请方提供）：“分枝杆菌蜡酸酯毒力因子的生物合成。结核分支杆菌复合体内或该复合体外的专性分支杆菌病原体和机会性分支杆菌病原体（即，非结核分枝杆菌[NTM]）是造成世界范围内大量发病率和死亡率的原因。分枝杆菌感染的治疗因分枝杆菌对许多抗生素的弹性而复杂化，所述弹性由独特的分枝杆菌细胞壁的渗透性屏障提供。由于获得性耐药性的增加，分枝杆菌感染也变得越来越难以治疗。多重耐药和广泛耐药的M。肺结核是全球性的威胁。多重耐药M.麻风病威胁着麻风病控制的未来。NTM感染呈上升趋势，耐药NTM在美国和国外日益受到关注。开发对抗耐药分枝杆菌上升所需的丰富治疗武器库需要利用常规和非常规药物靶标和治疗方法。在这种情况下，所需的分枝杆菌酶的生物合成（糖）脂质所需的毒力和参与强化细胞壁透性屏障是目标候选人，探索创新的辅助药物的开发添加到多药治疗，以改善临床结果。分枝杆菌二分枝杆菌蜡酸酯（DIM）是许多致病分枝杆菌（例如，M.结核复合体、M.麻风和几种NTM）。DIM是下调和破坏免疫机制、加强细胞壁通透性屏障、降低药物敏感性并且可能在宿主巨噬细胞中提供一层针对氧化防御的保护的主要毒力因子。拟议的项目将利用遗传和生物化学方法提供关于DIM生物合成的新机制知识。该项目将通过一个有四个子目标的重点目标和使用机会病原体M来进行。marinum作为DIM生产商的代表。M. marinum是M.结核复合体，经常被用来模拟M.结核病复杂的发病机制，并提供了更大的实验比其他DIM生产者的易处理性。剖析DIM生物合成将为探索开发阻断DIM合成的创新佐剂药物的长期目标铺平道路，从而有可能增强宿主防御能力并使DIM产生分枝杆菌对某些抗菌药物治疗（超）敏感。

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.