Abstract
The oral microflora is composed of both health-promoting as well as disease-initiating bacteria. Many of the disease-initiating bacteria are anaerobic and include organisms such as Porphyromonas gingivalis, Prevotella intermedia, Fusobacterium nucleatum, and Tannerella forsythia. Here we investigated a novel therapeutic, amixicile, that targets pyruvate:ferredoxin oxidoreductase (PFOR), a major metabolic enzyme involved in energy generation through oxidative decarboxylation of pyruvate. PFOR is present in these anaerobic pathogenic bacteria and thus we hypothesized that amixicile would effectively inhibit their growth. In general, PFOR is present in all obligate anaerobic bacteria, while oral commensal aerobes, including aerotolerant ones, such as Streptococcus gordonii, use pyruvate dehydrogenase to decarboxylate pyruvate. Accordingly, we observed that growth of the PFOR-containing anaerobic periodontal pathogens, grown in both monospecies as well as multispecies broth cultures was inhibited in a dose-dependent manner while that of S. gordonii was unaffected. Furthermore, we also show that amixicile is effective against these pathogens grown as monospecies and multispecies biofilms. Finally, amixicile is the first selective therapeutic agent active against bacteria internalized by host cells. Together, the results show that amixicile is an effective inhibitor of oral anaerobic bacteria and as such, is a good candidate for treatment of periodontal diseases.
Highlights
Periodontitis is an oral inflammatory disease that affects half of the United States adult population and disproportionally affects the aging population[1, 2]
Oral facultative and aerotolerant anaerobic bacteria such as A. actinomycetemcomitans and S. gordonii express pyruvate dehydrogenase (PDH), which is found in humans (Fig. 1)
These data suggest that P. gingivalis, P. intermedia, F. nucleatum, and T. forsythia should be susceptible to amixicile, whereas A. actinomycetemcomitans and S. gordonii would not, as they do not contain the amixicile drug target, pyruvate:ferredoxin oxidoreductase (PFOR)
Summary
Periodontitis is an oral inflammatory disease that affects half of the United States adult population and disproportionally affects the aging population[1, 2]. Most of the antibiotics currently used (such as clindamycin, tetracycline, and amoxicillin) are broad spectrum and eliminate both “health-promoting” and “disease-promoting” bacteria[15,16,17,18,19] This leaves the treated oral environment ripe for re-infection by periodontal disease-promoting pathogens, as they do not have to compete with resident microflora. NTZ is an FDA-approved therapeutic for the treatment of parasitic infections such as Cryptosporidium, Trichomonas, Entamoeba, and Giardia[23, 24] and shows in vitro activity against a wide range of strictly anaerobic bacteria[25, 26] These small molecules inhibit the activity of PFOR by outcompeting pyruvate for binding to the thiamine pyrophosphate (TPP) cofactor of PFOR in the active site[27]. The action of amixicile was not ablated by the presence of 10% saliva or serum, lending support to potential efficacy in treatment of periodontal disease
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