Targeting Non-mammalian Isoprenoid Biosynthesis

 描述（由申请人提供）：感染性疾病中抗生素耐药性的发生率日益增加，对人类健康构成严重威胁，并要求开发新的抗菌治疗方法。不可或缺的甲基异戊二烯磷酸（MEP）途径包括多种病原体中的七种酶靶点，包括超过一半的细菌病原体，这些病原体被CDC列为对公共卫生的严重或紧急威胁。尽管如此，只有IspC抑制剂磷咪霉素通过临床评价取得了进展，突出了缺乏临床上有用的药物靶向这一途径。我们的研究寻求新的方法来阻止人类病原体中必需的类异戊二烯的产生。拟议的研究将集中在MEP途径中未开发的靶点，包括由硫胺素二磷酸依赖性1-脱氧-D-木酮糖5-磷酸（DXP）合酶催化的第一步，以及由环二磷酸合酶IspF催化的第五步。第三个研究领域将集中于通过早期类异戊二烯生物合成的靶向通量。我们将采取多学科的方法：1）描绘DXP合酶催化和构象动力学的独特方面，可用于选择性抑制剂的设计，2）检查一个假定的前馈调节机制MEcDP生产的IspF作为一个潜在的新的抗菌靶标，和3）开发策略，以抑制流量通过MEP途径的早期步骤使用简单的底物类似物。我们的研究有望建立我们对独特酶行为的了解，这些酶行为代表了药理学干预的潜在点，这可能导致新的抗菌疗法的开发。

 DESCRIPTION (provided by applicant): The increasing occurrence of antimicrobial-resistance in infectious diseases poses a serious threat to human health, and demands the development of new antimicrobial therapies. The indispensable methylerythritol phosphate (MEP) pathway to isoprenoids comprises seven enzymatic targets in a wide variety of pathogens, including greater than half of bacterial pathogens prioritized by the CDC as serious or urgent threats to public health. Despite this, only the IspC inhibitor fosmidomycin has advanced through clinical evaluation, highlighting the lack of clinically useful agents targeting this pathway. Our research seeks new approaches to block essential isoprenoid production in human pathogens. The proposed studies will focus on under-developed targets in the MEP pathway, including the first step catalyzed by thiamin diphosphate-dependent 1-deoxy-D-xylulose 5-phosphate (DXP) synthase, and the fifth step catalyzed by cyclodiphosphate synthase IspF. A third area of research will focus on targeting flux through early stage isoprenoid biosynthesis. We will take multidisciplinary approaches to: 1) delineate the unique aspects of DXP synthase catalysis and conformational dynamics that can be exploited for selective inhibitor design, 2) examine a putative feed-forward regulatory mechanism for MEcDP production by IspF as a potential new antimicrobial target, and 3) develop strategies to inhibit flux through the early steps of the MEP pathway using simple substrate analogs. Our research is expected to build our knowledge of the unique enzyme behaviors that represent potential points for pharmacologic intervention, which could lead to the development of new antimicrobial therapies.