title: Oxantel disrupts polymicrobial biofilm development of periodontal pathogens.
abstract: Bacterial pathogens commonly associated with chronic periodontitis are the spirochete Treponema denticola and the Gram-negative, proteolytic species Porphyromonas gingivalis and Tannerella forsythia. These species rely on complex anaerobic respiration of amino acids, and the anthelmintic drug oxantel has been shown to inhibit fumarate reductase (Frd) activity in some pathogenic bacteria and inhibit P. gingivalis homotypic biofilm formation. Here, we demonstrate that oxantel inhibited P. gingivalis Frd activity with a 50% inhibitory concentration (IC50) of 2.2 μM and planktonic growth of T. forsythia with a MIC of 295 μM, but it had no effect on the growth of T. denticola. Oxantel treatment caused the downregulation of six P. gingivalis gene products and the upregulation of 22 gene products. All of these genes are part of a regulon controlled by heme availability. There was no large-scale change in the expression of genes encoding metabolic enzymes, indicating that P. gingivalis may be unable to overcome Frd inhibition. Oxantel disrupted the development of polymicrobial biofilms composed of P. gingivalis, T. forsythia, and T. denticola in a concentration-dependent manner. In these biofilms, all three species were inhibited to a similar degree, demonstrating the synergistic nature of biofilm formation by these species and the dependence of T. denticola on the other two species. In a murine alveolar bone loss model of periodontitis oxantel addition to the drinking water of P. gingivalis-infected mice reduced bone loss to the same level as the uninfected control.
authors.affiliation: Oral Health CRC, Melbourne Dental School, Bio21 Institute, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: Dashper
authors.forename: Neil
authors.initials: N
authors.lastname: O'Brien-Simpson
authors.forename: Sze Wei
authors.initials: SW
authors.lastname: Liu
authors.forename: Rita
authors.initials: R
authors.lastname: Paolini
authors.forename: Helen
authors.initials: H
authors.lastname: Mitchell
authors.forename: Katrina
authors.initials: K
authors.lastname: Walsh
authors.forename: Tanya
authors.initials: T
authors.lastname: D'Cruze
authors.forename: Brigitte
authors.initials: B
authors.lastname: Hoffmann
authors.forename: Deanne
authors.initials: D
authors.lastname: Catmull
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.forename: Eric
authors.initials: E
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D000969:Antinematodal Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D018441:Biofilms / Q000187:drug effects; D051379:Mice; D010518:Periodontitis / Q000382:microbiology; D016966:Porphyromonas gingivalis / Q000187:drug effects; D011715:Pyrantel / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013385:Succinate Dehydrogenase / Q000378:metabolism; D048373:Treponema denticola / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000969:Antinematodal Agents; D011715:Pyrantel; C003407:oxantel; D013385:Succinate Dehydrogenase