COMPLEX OF FPPS-PV

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们正在使用X射线和计算方法来指导分子的开发，以抑制金黄色葡萄球菌中橙色类胡萝卜素毒力因子葡萄糖素的形成。葡黄素生物合成的第一步是类异戊二烯的法尼基二磷酸(FPP)的两个分子缩合形成脱氢角鲨烯。在最近的初步工作中，我们发现膦磺酸盐(已开发的用于治疗高胆固醇血症的人角鲨烯合成酶抑制剂)也在200 NM水平上阻止金黄色葡萄球菌中葡萄糖素的生物合成。由此产生的金黄色葡萄球菌(金黄色葡萄球菌=金黄色)是白色的，在小鼠中不具感染性，可被中性粒细胞杀死，因为它们降低了对活性氧物种(ROS)的防御能力。在目标1中，我们将开发更有效和更有选择性的化合物，使用核磁共振、X射线和计算方法来指导设计过程。如果成功，这项工作将具有重要意义，因为越来越多的毒力、社区获得的金黄色葡萄球菌和甲氧西林耐药菌株正在对基于ROS的杀戮产生高度抗药性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We are using x-ray and computational methods to guide the development of molecules that inhibit formation of the orange carotenoid virulence factor, staphyloxanthin, in S. aureus. The first committed step in staphyloxanthin biosynthesis is the condensation of two molecules of the isoprenoid farnesyldiphosphate (FPP) to form dehydrosqualene. In recent preliminary work, we have discovered that phosphonosulfonates (human squalene synthase inhibitors which have been developed to treat hypercholesterolemia) also block staphyloxanthin biosynthesis in S. aureus, at 200 nM levels. The resulting S. aureus (L. aureus=golden) are white, non-infective in mice and are killed by neutrophils, since they have decreased defenses to reactive oxygen species (ROS). In Aim 1, we will develop more potent and selective compounds, using NMR, x-ray and computational methods to guide the design process. If successful, this work would be of importance given the increasing number of virulent, community acquired S. aureus and methicillin resistant strains which are becoming highly resistant to ROS based killing.