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.
[Show abstract][Hide abstract] 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.
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.
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.
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 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Transition metals including iron and manganese are necessary for life because of their ability to donate and accept electrons. Approximately one-third of all proteins require essential transition metal ions to perform catalytic, structural and regulatory functions. These essential metal ions react differently to the presence of oxygen radicals with iron directly involved in the formation of toxic reactive oxygen species, whilst manganese can protect against oxidative stress. Highlight Anaerobic bacterial species have been poorly studied with regard to transition metal homoeostasis and behave differently in many respects when compared with aerobic or aerotolerant species. To optimise catabolism whilst protecting themselves from unwanted reactions bacterial cells must maintain intracellular metal levels in a very narrow range that varies, dependent on the environment. To maintain metal ion homoeostasis, bacteria have evolved complex regulatory mechanisms of metal uptake, secretion and storage. In this review we examine how iron, haem and manganese availability dictate the lifestyle and virulence of the anaerobic Gram-negative, periodontal pathogen Porphyromonas gingivalis. Conclusion P. gingivalis has novel haem, iron and manganese transporters and metalloregulatory proteins that enable it to switch rapidly between an energy efficient iron-dependent virulent phase and a protective manganese-dependent survival phase.
Journal of Oral Biosciences 01/2015; 93(2). DOI:10.1016/j.job.2014.12.003
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