Targeting Non-mammalian Isoprenoid Biosynthesis

描述(申请人提供)：人类病原体对抗感染药物的抗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。甲基赤藓糖醇磷酸(MEP)合成异戊二烯的必需途径在人类病原体中广泛存在，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。这一途径中的几种酶可以催化前所未有的反应，使它们成为开发选择性抑制剂的目标。我们的长期目标是了解MEP途径中的催化作用，以开发针对病原体中类异戊二烯生物合成的抑制剂。这项建议描述了三种有趣的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)的酶的机理研究和抑制剂开发。具体目标2的目标是了解DXP合酶在C-N键形成中的催化作用，以生成医学上有用的异羟肟酸化合物类。针对这些酶开发的抗感染剂有可能广泛影响致命传染病的治疗。 公共卫生相关性：人类病原体的耐药性是一个全球卫生问题，需要持续努力制定新的战略来治疗威胁生命的感染。拟议的研究检查了在人类病原体中广泛存在的机械上有趣的必要的甲基赤藓糖醇磷酸途径酶。对这些酶的机理研究将导致新的抗感染药物的开发。

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.