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.