Traditional antimicrobial therapies for periodontitis (PD) have long focused on non-selective and direct approaches. Professional cleaning of the subgingival biofilm by instrumentation of dental root surfaces, known as scaling and root planning (SRP), is the mainstay of periodontal therapy and is indisputably effective. Non-physical approaches used as adjuncts to SRP, such as chemical and biological agents, will be the focus of this review. In this regard, traditional agents such as oral antiseptics and antibiotics, delivered either locally or systemically, were briefly reviewed as a backdrop. While generally effective in winning the “battle” against PD in the short term, by reducing its signs and symptoms, patients receiving such therapies are more susceptible to recurrence of PD. Moreover, the long-term consequences of such therapies are still in question. In particular, concern about chronic use of systemic antibiotics and their influence on the oral and gut microbiota is warranted, considering antibiotic resistance plasmids, and potential transfer between oral and non-oral microbes. In the interest of winning the “battle and the war”, new more selective and targeted antimicrobials and biologics for PD are being studied. These are principally indirect, blocking pathways involved in bacterial colonization, nutrient acquisition, inflammation or cellular invasion without directly killing the pathogens. This review will focus on current and prospective antimicrobial therapies for PD, emphasizing therapies that act indirectly on the microbiota, with clearly defined cellular and molecular targets.

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Porphyromonas gingivalis (P. gingivalis) is a unique pathogen implicated in severe forms of periodontitis (PD), a disease that affects around 50% of the US population. P. gingivalis is equipped with a plethora of virulence factors that it uses to exploit its environment and survive. These include distinct fimbrial adhesins that enable it to bind to other microbes, colonize inflamed tissues, acquire nutrients, and invade cells of the stroma and immune system. Most notable for this review is its ability to invade dendritic cells (DCs), which bridge the innate and adaptive immune systems. This invasion process is tightly linked to the bridging functions of resultant DCs, in that it can disable (or stimulate) the maturation function of DCs and cytokines that are secreted. Maturation molecules (e.g., MHCII, CD80/CD86, CD40) and inflammatory cytokines (e.g., IL-1b, TNFa, IL-6) are essential signals for antigen presentation and for proliferation of effector T-cells such as Th17 cells. In this regard, the ability of P. gingivalis to coordinately regulate its expression of major (fimA) and minor (mfa-1) fimbriae under different environmental influences becomes highly relevant. This review will, therefore, focus on the immunoregulatory role of P. gingivalis fimbriae in the invasion of DCs, intracellular signaling, and functional outcomes such as alveolar bone loss and immune senescence.

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