title: Repurposing Toremifene for Treatment of Oral Bacterial Infections.
abstract: The spread of antibiotic resistance and the challenges associated with antiseptics such as chlorhexidine have necessitated a search for new antibacterial agents against oral bacterial pathogens. As a result of failing traditional approaches, drug repurposing has emerged as a novel paradigm to find new antibacterial agents. In this study, we examined the effects of the FDA-approved anticancer agent toremifene against the oral bacteriaPorphyromonas gingivalisandStreptococcus mutansWe found that the drug was able to inhibit the growth of both pathogens, as well as prevent biofilm formation, at concentrations ranging from 12.5 to 25 μM. Moreover, toremifene was shown to eradicate preformed biofilms at concentrations ranging from 25 to 50 μM. In addition, we found that toremifene preventsP. gingivalisandS. mutansbiofilm formation on titanium surfaces. A time-kill study indicated that toremifene is bactericidal againstS. mutansMacromolecular synthesis assays revealed that treatment with toremifene does not cause preferential inhibition of DNA, RNA, or protein synthesis pathways, indicating membrane-damaging activity. Biophysical studies using fluorescent probes and fluorescence microscopy further confirmed the membrane-damaging mode of action. Taken together, our results suggest that the anticancer agent toremifene is a suitable candidate for further investigation for the development of new treatment strategies for oral bacterial infections.
authors.affiliation: KU Leuven, Centre of Microbial and Plant Genetics, Department of Microbial and Molecular Systems, Leuven, Belgium.
authors.forename: Evelien
authors.initials: E
authors.lastname: Gerits
authors.affiliation: KU Leuven, Centre of Microbial and Plant Genetics, Department of Microbial and Molecular Systems, Leuven, Belgium.
authors.forename: Valerie
authors.initials: V
authors.lastname: Defraine
authors.affiliation: UZ Leuven, Restorative Dentistry-KU Leuven, BIOMAT, Department of Oral Health Sciences, Leuven, Belgium.
authors.forename: Katleen
authors.initials: K
authors.lastname: Vandamme
authors.affiliation: KU Leuven, Centre of Microbial and Plant Genetics, Department of Microbial and Molecular Systems, Leuven, Belgium.|VIB, Department of Plant Systems Biology, Ghent, Belgium.
authors.forename: Kaat
authors.initials: K
authors.lastname: De Cremer
authors.affiliation: KU Leuven, Centre of Microbial and Plant Genetics, Department of Microbial and Molecular Systems, Leuven, Belgium.
authors.forename: Katrijn
authors.initials: K
authors.lastname: De Brucker
authors.affiliation: KU Leuven, Centre of Microbial and Plant Genetics, Department of Microbial and Molecular Systems, Leuven, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Thevissen
authors.affiliation: KU Leuven, Centre of Microbial and Plant Genetics, Department of Microbial and Molecular Systems, Leuven, Belgium.|VIB, Department of Plant Systems Biology, Ghent, Belgium.
authors.forename: Bruno P A
authors.initials: BP
authors.lastname: Cammue
authors.affiliation: KU Leuven, Centre of Microbial and Plant Genetics, Department of Microbial and Molecular Systems, Leuven, Belgium.
authors.forename: Serge
authors.initials: S
authors.lastname: Beullens
authors.affiliation: KU Leuven, Centre of Microbial and Plant Genetics, Department of Microbial and Molecular Systems, Leuven, Belgium.|imec, Smart Systems and Emerging Technologies Unit, Department of Life Science Technologies, Leuven, Belgium.
authors.forename: Maarten
authors.initials: M
authors.lastname: Fauvart
authors.affiliation: KU Leuven, Centre of Microbial and Plant Genetics, Department of Microbial and Molecular Systems, Leuven, Belgium.
authors.forename: Natalie
authors.initials: N
authors.lastname: Verstraeten
authors.affiliation: KU Leuven, Centre of Microbial and Plant Genetics, Department of Microbial and Molecular Systems, Leuven, Belgium Jan.Michiels@kuleuven.be.
authors.forename: Jan
authors.initials: J
authors.lastname: Michiels
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D002463:Cell Membrane Permeability / Q000187:drug effects; D003773:Dental Plaque / Q000188:drug therapy / Q000382:microbiology; D058492:Drug Repositioning; D024901:Drug Resistance, Multiple, Bacterial / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D010518:Periodontitis / Q000188:drug therapy / Q000382:microbiology; D016966:Porphyromonas gingivalis / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D013295:Streptococcus mutans / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D014025:Titanium / Q000032:analysis; D017312:Toremifene / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D018931:Antineoplastic Agents, Hormonal; D017312:Toremifene; D014025:Titanium
keywords: Porphyromonas gingivalis; Streptococcus mutans; biofilms; oral infections; toremifene