Oxantel Disrupts Polymicrobial Biofilm Development of Periodontal Pathogens
ABSTRACT Bacterial pathogens commonly associated with chronic periodontitis are the spirochaete 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 an IC50 of 2.2 μM and planktonic growth of T. forsythia with a minimal inhibitory concentration of 295 μM, but 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 haem 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.
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ABSTRACT: Objectives To investigate the suggested role of Porphyromonas gingivalis peptidylarginine deiminase (PAD) in the relationship between the aetiology of periodontal disease and experimentally induced arthritis and the possible association between these two conditions. Methods A genetically modified PAD-deficient strain of P. gingivalis W50 was produced. The effect of this strain, compared to the wild type, in an established murine model for experimental periodontitis and experimental arthritis was assessed. Experimental periodontitis was induced following oral inoculation with the PAD-deficient and wild type strains of P. gingivalis. Experimental arthritis was induced via the collagen antibody induction process and was monitored by assessment of paw swelling and micro-CT analysis of the radio-carpal joints. Experimental periodontitis was monitored by micro CT scans of the mandible and histological assessment of the periodontal tissues around the mandibular molars. Serum levels of anti-citrullinated protein antibodies (ACPA) and P. gingivalis were assessed by ELISA. Results The development of experimental periodontitis was significantly reduced in the presence of the PAD-deficient P. gingivalis strain. When experimental arthritis was induced in the presence of the PAD-deficient strain there was less paw swelling, less erosive bone damage to the joints and reduced serum ACPA levels when compared to the wild type P. gingivalis inoculated group. Conclusion This study has demonstrated that a PAD-deficient strain of P. gingivalis was associated with significantly reduced periodontal inflammation. In addition the extent of experimental arthritis was significantly reduced in animals exposed to prior induction of periodontal disease through oral inoculation of the PAD-deficient strain versus the wild type. This adds further evidence to the potential role for P. gingivalis and its PAD in the pathogenesis of periodontitis and exacerbation of arthritis. Further studies are now needed to elucidate the mechanisms which drive these processes.PLoS ONE 06/2014; 9(6):e100838. DOI:10.1371/journal.pone.0100838 · 3.53 Impact Factor