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.