Oxantel Disrupts Polymicrobial Biofilm Development of Periodontal Pathogens

Abstract

ABSTRACTBacterial pathogens commonly associated with chronic periodontitis are the spirocheteTreponema denticolaand the Gram-negative, proteolytic speciesPorphyromonas gingivalisandTannerella 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 inhibitP. gingivalishomotypic biofilm formation. Here, we demonstrate that oxantel inhibitedP. gingivalisFrd activity with a 50% inhibitory concentration (IC50) of 2.2 μM and planktonic growth ofT. forsythiawith a MIC of 295 μM, but it had no effect on the growth ofT. denticola. Oxantel treatment caused the downregulation of sixP. gingivalisgene 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 thatP. gingivalismay be unable to overcome Frd inhibition. Oxantel disrupted the development of polymicrobial biofilms composed ofP. gingivalis,T. forsythia, andT. denticolain 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 ofT. denticolaon the other two species. In a murine alveolar bone loss model of periodontitis oxantel addition to the drinking water ofP. gingivalis-infected mice reduced bone loss to the same level as the uninfected control.