Targeting Non-mammalian Isoprenoid Biosynthesis

描述（由申请人提供）：人类病原体对抗感染药物的耐药性对人类健康构成严重威胁，需要持续努力开发新的治疗方法。类异戊二烯生物合成必需的甲基赤藓醇磷酸（MEP）途径广泛存在于人类病原体中，包括由结核分枝杆菌和恶性疟原虫引起的一些最致命的感染。该途径中的一些酶催化了前所未有的反应，使它们成为开发选择性抑制剂的特别有吸引力的目标。我们的长期目标是了解MEP途径的催化作用，从而开发针对病原体中类异戊二烯生物合成的抑制剂。本提案描述了对三种有趣的MEP途径酶，IspG， DXP合成酶和IspF的研究。具体目标1和3侧重于产生和利用环二磷酸中间体甲基赤藓糖醇环二磷酸（MEcPP）的酶的机制研究和抑制剂开发。特异性目标2的目标是了解DXP合成酶在C-N键形成中的催化作用，以生成药用羟肟酸化合物类。针对这些酶开发的抗感染药物有可能广泛影响致命传染病的治疗。

DESCRIPTION (provided by applicant): Resistance of human pathogens to anti-infective agents poses a serious threat to human health and requires sustained efforts to develop new therapies. The essential methylerythritol phosphate (MEP) pathway for isoprenoid biosynthesis is widespread in human pathogens, including some of the most deadly infections caused by M. tuberculosis and P. falciparum. Several of the enzymes in this pathway catalyze unprecedented reactions, making them particularly attractive as targets for the development of selective inhibitors. Our long term goal is to understand catalysis in the MEP pathway toward the development of inhibitors targeting isoprenoid biosynthesis in pathogens. This proposal describes studies to examine three intriguing MEP pathway enzymes, IspG, DXP synthase and IspF. Specific Aims 1 and 3 focus on mechanistic studies and inhibitor development of the enzymes that generate and utilize cyclodiphosphate intermediate, methylerythritol cyclodiphosphate (MEcPP). The goal of Specific Aim 2 is to understand catalysis of DXP synthase in C-N bond formation to generate the medicinally useful hydroxamic acid compound class. Anti-infective agents developed to target these enzymes have the potential to broadly impact the treatment of deadly infectious diseases. PUBLIC HEALTH RELEVANCE: Drug resistance in human pathogens is a global health concern requiring sustained efforts to develop new strategies for treatment of life threatening infections. The proposed studies examine the mechanistically intriguing essential methylerythritol phosphate pathway enzymes which are widespread in human pathogens. Mechanistic studies of these enzymes will lead to the development of new anti-infective agents.