BIOSYNTHESIS OF MYCOBACTERIAL DIMYCOCEROSATE ESTER VIRULENCE FACTORS

描述（由申请人提供）：“分枝杆菌粘菌酯毒力因子的生物合成。在结核分枝杆菌复合体内或复合体外（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是造成世界范围内大量发病率和死亡率的原因。由于独特的分枝杆菌细胞壁的渗透性屏障使分枝杆菌对许多抗生素具有弹性，因此分枝杆菌感染的治疗变得复杂。由于获得性耐药的增加，分枝杆菌感染也变得越来越难以治疗。耐多药和广泛耐药结核分枝杆菌菌株构成全球威胁。麻风分枝杆菌耐多药菌株有可能危及麻风控制的未来。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增加所需的丰富治疗武器库需要利用传统和非传统的药物靶点和治疗方法。从这个角度来看，用于毒力所需的（糖）脂类生物合成和参与细胞壁渗透性屏障强化的分枝杆菌酶是探索开发创新辅助药物以改善多药治疗临床结果的靶标候选者。分枝杆菌二真菌酸酯（DIMs）是许多致病性分枝杆菌（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质（以下分别称为PDIMs和PGLs）。DIMs是下调和破坏免疫机制、增强细胞壁通透性屏障、降低药物敏感性的主要毒力因子，可能对宿主巨噬细胞的氧化防御提供一层保护。该项目将利用遗传和生物化学方法来提供有关DIMs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进行，并使用机会致病菌海洋分枝杆菌作为DIM生产者的代表。海洋分枝杆菌是结核分枝杆菌复合体最近的遗传亲戚，经常被用来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生产者具有更大的实验可追踪性。解剖DIM的生物合成将为探索开发阻断DIM合成的创新辅助药物铺平道路，从而有可能增强宿主防御能力，并使产生DIM的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.