Interproximal and horizontal alveolar bone loss in mouse models are seen in coinfections involving P. gingivalis and Treponema denticola. The role of P. gingivalis as a community activist in periodontitis is seen in specific pathogen-free mouse models of periodontal infections. In these models, P. gingivalis inoculation causes significant bone loss, which is a significant characteristic of the disease. In contrast, germ free mice inoculated with a P. gingivalis monoinfection incur no bone loss, indicating that P. gingivalis alone cannot induce periodontitis.
T. denticola is associated with the incidence and severity of human periodontal disease. Having elevated T. denticola levels in the mouth is considered one of the main etiological agents of periodontitis. T. denticola is related to the syphilis-causing obligate human pathogen, Treponema pallidum subsp. pallidum.
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New approaches to combat Porphyromonas gingivalis biofilms
Quorum sensing inhibitors
Quorum sensing inhibitors have been presented as promising alternatives for the treatment of biofilm-related infections, as they do not affect growth and thus have a low potential for resistance development . In this respect, quorum sensing inhibitors (5Z)-4-bromo-5-(bromomethylene)-2(5 H)-furanone (2 mM) and D-ribose (50 mM) have been shown to reduce both P. gingivalis monospecies and F. nucleatum and P. gingivalis mixed-species biofilm development . Furthermore, these agents are not toxic for human monocytic cells and human gingival fibroblasts at tested concentrations, and do not stimulate production of proinflammatory factors. In addition, these inhibitors remain active against P. gingivalis under in vivo conditions, making them suitable candidates for further development into anti–P. gingivalis drugs .
Antimicrobial peptides are widely proposed as a new source of future antibiotics, as they often have broad-spectrum activity and a low tendency for resistance development . An overview of the currently known antimicrobial peptides that show antibiofilm activity against P. gingivalis is given in Table 1.
Plant-derived antibacterial agents
To overcome the alarming scarcity of new antibiotic classes, several recent studies have focused on finding new antibiotics from unexplored natural sources . In this context, plants have proved to be a good new source for finding new antibacterial agents. This is not surprising, as plants are frequently exposed to bacterial infections and thus have developed various defense mechanisms to combat bacterial pathogens. Table 2 gives an overview of new antibiotics derived from plants that affect P. gingivalis biofilm formation.
Non-dialysable material from cranberrry juice Vaccinium macrocarpon 62.5 µg/mL 
A-type cranberry proanthocyanidins Vaccinium macrocarpon 50 µg/mL 
Prenylated flavonoids Epimedium species 1.25 µM 
Lacinartin Citrus fruits 50 µg/mL 
Tea catechin epigallocatechin gallate Camellia sinensis (tea plant) 10 µg/mL 
Essential oils Medicinal and aromatic plants (Aloysia gratissima, Coriandrum sativum L., Muhlenbergia glomerata, Cyperus articulatus, and Lippia sidoides) 0.125–1 mg/mL 
Essential oil Shiitake mushroom (Lentinula edodes) 0.97 µg/mL 
Carvacrol Thymus vulgaris, Carum copticum, and oreganum species 1% 
Roselle calyx extract Hibiscus sabdariffa L. 0.9 mg/mL 
Capsaicin Capsicum plants (chili peppers) 32 µg/mL 
The non-dialyzable material fraction of cranberry juice rich in proanthocyanidins and A-type cranberry proanthocyanidins extracted from cranberry juice concentrate were shown to exhibit activity against P. gingivalis biofilms [99,100]. The latter fraction was also found to affect adherence to oral epithelial cells negatively and have anti-inflammatory activities by inhibiting the secretion of interleukin-8 and chemokine ligand 5 . Of note, the activity of these A-type cranberry proanthocyanidin can be increased by combination therapy with Licochalcone A, a major chalcone in licorice root .
A number of prenylated flavonoids isolated from Epimedium species were reported to inhibit biofilm formation by P. gingivalis and to interfere with Rgp and Kgp gingipain activity .
Lacinartin derived from Citrus fruits and Tea catechin derived from Camellia sinensis have been demonstrated to inhibit biofilm formation of P. gingivalis biofilms and to desorb pre-formed biofilms [102,103]. Furthermore, Lacinartin negatively affected adherence to epithelial cells.
Extracted oils obtained from plants also possess activity against P. gingivalis biofilms. Indeed, essential oils extracted from medicinal and aromatic plants such as Aloysia gratissima, Coriandrum sativum L., Muhlenbergia glomerata, Cyperus articulatus, Lippia sidoides, and from shiitake have been reported to inhibit P. gingivalis biofilm formation [104,105]. Additionally, carvacrol, a monoterpene phenol present in the volatile oils of Thymus vulgaris, Carum copticum, and oreganum species, inhibits P. ginigvalis biofilm formation on titanium implant material .
Recent studies revealed the antibiofilm effects of roselle calyx extract and capsaicin, which is the active compound of Capsicum plants (chili peppers) against P. gingivalis [107,108]. The latter also reduces the viability of pre-formed biofilms and has an inhibitory effects on both inflammatory cytokine secretion and in vitro osteoclastogenesis.
Saccharides of marine origin
In recent years, the marine environment has been explored as a source for finding new natural antibacterial agents. In this context, OligoG, which is an oligosaccharide derived from brown algae alginate, was found to reduce biofilm formation of P. gingivalis drastically . Furthermore, treatment of titanium surfaces with triclosan combined with OligoG significantly decreases P. gingivalis attachment to titanium surfaces compared with treatment of the surfaces with triclosan alone.
Chitosan, which is a natural linear polysaccharide derived from chitin present in the exoskeleton of marine crustaceans, has also been reported to have antibiofilm activities against P. gingivalis .
Sugar alcohols are commonly used in place of sucrose as non-cariogenic sweeteners. However, little is known about their activity against periodontal bacteria . A recent study reported that the sugar alcohol erythritol effectively inhibits P. gingivalis biofilm formation and reduces P. gingivalis accumulation onto S. gordonii substrata . The authors concluded that erythritol acts via several pathways, including suppression of growth resulting from DNA and RNA depletion, attenuated extracellular matrix production, and alterations of dipeptide acquisition and amino acid metabolism.
Drug repurposing has increasingly been applied over the last years as a strategy to uncover new antibiotics. This strategy has some advantages over de novo drug discovery, including known toxicological and pharmacological profiles, thereby accelerating the drug-development process significantly . In this context, we recently screened a drug-repositioning library (NIH Clinical Collection) to identify new compounds that show activity against P. gingivalis . The screen led to the discovery of three new molecules that show antibiofilm activity against P. gingivalis: zafirlukast, an anti-asthmatic drug, toremifene, an anti-cancer drug, and N-(4-Hydroxyphenyl)arachidonylamide (AM404), an active metabolite of paracetamol [117–119]. The anthelmintic drug oxantel, which is typically used for the treatment of intestinal worms, has also been proven to inhibit biofilm formation by P. gingivalis significantly by inhibition of fumarate reductase. Furthermore, oxantel is more effective than the conventional antibiotic metronidazole in inhibiting P. gingivalis biofilms . In a follow-up study, it was demonstrated that oxantel can disrupt the development of polymicrobial biofilms composed of P. gingivalis, Tannerella forsythia, and T. denticola in a concentration-dependent manner .
The coating of titanium surfaces with antibacterial agents has recently been explored as a new strategy for the prevention of peri-implant infections . A number of studies have investigated the potential of antibacterial peptides to be used in coating applications. Indeed, coatings that are functionalized with GL13K (derived from the human salivary protein Parotid Secretory Protein [BPIFA2]), histatin-5 (belonging to a family of peptides secreted by the major salivary glands), lactoferricin (generated by gastric pepsin cleavage of lactoferrins), and synthetic peptide Tet213 have been demonstrated to strongly reduce P. gingivalis biofilm formation [123–125].
The antibiofilm activity of titanium surfaces coated with silver has also been explored. As such, titanium surfaces coated with silver-hydroxyapatite/titania nanocomposites have been shown to act in both a bactericidal and anti-adhesive way against P. gingivalis . In addition, the potential of silver- and gallium-doped phosphate-based glasses to inhibit growth of P. gingivalis–S. gordonii dual-species biofilms has been demonstrated . Furthermore, a follow-up study showed that the gallium-doped phosphate-based glasses remain active against P. gingivalis under in vivo conditions .
In addition, bifunctional coatings with both antibacterial and pro-osteodifferentiation capabilities have been developed. Simvastatin is known to increase the osteogenic capability of mesenchymal stem cells, while metronidazole is an antimicrobial agent that has excellent activity against strict anaerobic bacteria. Integration of these drugs into a calcium phosphate coating for titanium surfaces prevents the growth of P. gingivalis and increases osteogenic cell differentiation .
In recent years, a significant number of new compounds with antibiofilm activity against P. gingivalis have been identified. Unfortunately, to our knowledge, only one compound has progressed to clinical trials: the antibacterial peptide lactoferrin . Different factors may explain the limited availability of new antibacterial drugs. For example, in spite of the promising results of the above-mentioned antibacterial peptides, there are still some challenges to their applications, such as potential toxicity, susceptibility to proteases, and high production costs . As for the natural products interfering with P. gingivalis biofilm formation, limited information is currently present on their mode of action and their cytotoxicity. In addition, the active concentrations of some plant-derived compounds are up to 1,000 times higher than conventional antibiotics, indicating limited antibacterial activity [83,84,87]. Regarding the surface coating strategies to prevent biofilm formation on implants, there still exists a great discrepancy between the suggested strategies and their clinical applications . Furthermore, potential limitations of these coatings such as toxicity and hampered antibacterial activity under in vivo conditions should be tackled in future studies [131,132].
Thus, further mode-of-action studies, comprehensive toxicity analyses, and in vivo tests will be necessary to reveal fully the potential of newly discovered antibacterial agents to be used in the treatment of oral infections. In addition, a broader knowledge of the regulatory and molecular mechanisms behind P. gingivalis biofilm formation may further accelerate the development of future strategies for treatment of P. gingivalis–associated infections.
“Double blind studies have shown that folic acid can significantly reduce gum inflammation,” according to the Institute for Optimum Nutrition. This supplement is particularly important for pregnant women, as well as those who take contraceptive pills.
Other studies have identified Co Q10, folic acid and zinc as beneficial to fighting gum disease when applied topically. Folic acid can reduce gum inflammation and help them become more resilient to dental plaque and anaerobic bacteria, two of the primary culprits responsible for tooth decay, gum disease and bad breath. Folic acid helps to reduce gum bleeding, which is one of the most common signs of gum disease.
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