COMPLEX OF FPPS-PV

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们正在使用X射线和计算方法来指导抑制S.金黄色。葡萄黄素生物合成的第一个关键步骤是两个类异戊二烯法尼基二磷酸（FPP）分子缩合形成脱氢角鲨烯。在最近的初步工作中，我们发现膦酰基磺酸盐（已开发用于治疗高胆固醇血症的人角鲨烯合酶抑制剂）也阻断S.金黄色葡萄球菌，在200 nM水平。结果S。金黄色（L.金黄色=金黄色）是白色的，在小鼠中是非感染性的，并且被嗜中性粒细胞杀死，因为它们降低了对活性氧（ROS）的防御。在目标1中，我们将开发更有效和选择性的化合物，使用NMR，X射线和计算方法来指导设计过程。如果成功，这项工作将是重要的，因为越来越多的有毒，社区获得的S。金黄色葡萄球菌和甲氧西林抗性菌株，其对基于ROS的杀伤具有高度抗性。

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.