ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2021
Bisphosphonate inhibitors of squalene synthase protect cells against cholesterol-dependent cytolysins.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 14 citations in OpenAlex.
- Exploitation of cholesterol-dependent cytolysins for targeted biosensing and therapeutic systems.Drug delivery and translational research · 2026Review
- The Contribution of Cholesterol and Squalene Synthase in Cancer: Molecular Mechanisms, Lipid Rafts and Therapeutic Approaches.Medicinal research reviews · 2026Review
- Cholesterol metabolism and cancer: Molecular mechanisms, immune regulation and an epidemiological perspective (Review).International journal of molecular medicine · 2025Review
- Synthesis of Amino-Pharmaceuticals (Basel, Switzerland) · 2025Review
- Lipid-Centric Approaches in Combating Infectious Diseases: Antibacterials, Antifungals and Antivirals with Lipid-Associated Mechanisms of Action.Antibiotics (Basel, Switzerland) · 2023Review
- Review
- Statins as Potential Preventative Treatment of ETX and Multiple Pore-Forming Toxin-Induced Diseases.International journal of molecular sciences · 2023Article
- Glucocorticoids increase tissue cell protection against pore-forming toxins from pathogenic bacteria.Communications biology · 2023Article
- Oxysterols Protect Epithelial Cells Against Pore-Forming Toxins.Frontiers in immunology · 2022Article
- Oxysterols protect bovine endometrial cells against pore-forming toxins from pathogenic bacteria.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Bisphosphonate inhibitors of squalene synthase protect cells against cholesterol-dependent cytolysins.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Certain species of pathogenic bacteria damage tissues by secreting cholesterol-dependent cytolysins, which form pores in the plasma membranes of animal cells. However, reducing cholesterol protects cells against these cytolysins. As the first committed step of cholesterol biosynthesis is catalyzed by squalene synthase, we explored whether inhibiting this enzyme protected cells against cholesterol-dependent cytolysins. We first synthesized 22 different nitrogen-containing bisphosphonate molecules that were designed to inhibit squalene synthase. Squalene synthase inhibition was quantified using a cell-free enzyme assay, and validated by computer modeling of bisphosphonate molecules binding to squalene synthase. The bisphosphonates were then screened for their ability to protect HeLa cells against the damage caused by the cholesterol-dependent cytolysin, pyolysin. The most effective bisphosphonate reduced pyolysin-induced leakage of lactate dehydrogenase into cell supernatants by >80%, and reduced pyolysin-induced cytolysis from >75% to <25%. In addition, this bisphosphonate reduced pyolysin-induced leakage of potassium from cells, limited changes in the cytoskeleton, prevented mitogen-activated protein kinases cell stress responses, and reduced cellular cholesterol. The bisphosphonate also protected cells against another cholesterol-dependent cytolysin, streptolysin O, and protected lung epithelial cells and primary dermal fibroblasts against cytolysis. Our findings imply that treatment with bisphosphonates that inhibit squalene synthase might help protect tissues against pathogenic bacteria that secrete cholesterol-dependent cytolysins.
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