Bisphosphonate inhibitors of squalene synthase protect cells against cholesterol‐dependent cytolysins

Certain species of pathogenic bacteria damage tissues by secreting cholesterol-dependent cytolysins, which form pores in the plasma membranes animal cells. However, reducing cholesterol protects cells against these cytolysins. As first committed step biosynthesis is catalyzed squalene synthase, we explored whether inhibiting this enzyme protected We synthesized 22 different nitrogen-containing bisphosphonate molecules that were designed to inhibit synthase. Squalene synthase inhibition was quantified using a cell-free assay, and validated computer modeling binding The bisphosphonates then screened for their ability protect HeLa caused cytolysin, pyolysin. most effective reduced pyolysin-induced leakage lactate dehydrogenase into cell supernatants >80%, cytolysis from >75% <25%. In addition, potassium cells, limited changes cytoskeleton, prevented mitogen-activated protein kinases stress responses, cellular cholesterol. also another streptolysin O, lung epithelial primary dermal fibroblasts cytolysis. Our findings imply treatment with might help secrete