Periodontitis (PD) is a significant public health challenge with a high prevalence and noticeable socio-economic impacts. PD significantly affects patients’ quality of life. It is reported that, over the last decade, the prevalence of PD has reached nearly 60%, which is an increased compare to the same time period in the past (Trindade et al., 2023). PD is a chronic inflammatory condition, primarily caused by the formation of the microbial on dental surfaces, which damages the soft tissue surrounding the teeth. The biofilm consists of a complex community of microorganisms surrounded by an extracellular matrix of biological macromolecules. Biofilm is highly resistant to antimicrobial drugs and host immunity mechanisms. An imbalance in the microbial composition of biofilms, triggers host’s immune response, which leading to a chronic inflammatory condition. Gingivitis is a mild and reversible form of inflammation. If not treated properly, it can progress to PD, a chronic condition that can eventually lead to the entry of bacteria or their byproducts into the bloodstream. This, in turn, triggers the host’s inflammatory response through various mechanisms (Schenkein et al., 2020; Zhang et al., 2022). PD is characterized by damage to the periodontal ligament, pockets formation, and resorption of alveolar bone. These symptoms are induced by the host’s inflammatory response to bacterial biofilms, which express bacterial virulence factors (Preshaw and Bissett, 2019). Cytokines and immune mediators play a crucial role in the progression of PD by regulating inflammatory signals that control local inflammation and tissue destruction (Neurath and Kesting, 2024). The long-lasting presence of plaque on the surface of teeth leads to its migration into the neighboring periodontal tissues and stimulates the infiltration of host immune cells. The progression of PD is often affected by life style factors, such as deficient oral hygiene and smoking, compounded with genetic and disease-related compromise of the body’s immune response (Gao et al., 2018; Jensen et al., 2018; Deo and Deshmukh, 2019). The most common pathogens that caused PD are Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia (Saquib et al., 2021). Understanding the microbiology and pathogenesis of PD, as well as researching treatment options and drug resistance of the causative agents, will greatly improve the effectiveness of treatment. Currently there are few studies that comprehensively outline the microbiological aspects, inflammatory pathways involved in pathogenesis, antibiotic resistance, virulence factors of the causative microbial agents, and alternative treatment options for PD. The aim of the present study was to discuss the main bacteria involved in PD and their interaction of these bacteria with the immune response. We also provided an overview of the pathogenesis of bacteria in periodontitis and antibiotic treatment and emergence of antibiotics resistance. In this literature review, data on microbiology, pathogenesis, microbial resistance, and treatment of PD were gathered from databases including Google Scholar, Scopus, and PubMed. Searches were conducted using keywords such as “PD microbiology,” “PD pathogenesis,” “PD treatment,” and “antimicrobial resistance in PD-causing pathogens.” All English language articles retrieved were independently reviewed by two individuals.

The prolonged presence of plaque on the surface of teeth causes it to migrate into the surrounding periodontal tissues. This migration stimulates the infiltration of host immune cells, particularly polymorphonuclear neutrophils (PMNs), from the blood to the site of infection. It has been proposed that severe forms of PD, which primarily affect young individuals previously categorized as having “aggressive periodontitis” (AgPD) or grade 3 periodontitis (involving resorption of ≥2 mm over five years), may be associated with more unfavorable impacts compared to the more prevalent form known as “chronic periodontitis” (CPD) (Borilova Linhartova et al., 2020; Fuller et al., 2020). AgPD cases are commonly reported in individuals under the age of 30 years and exhibit a rapid progression that poses challenges in treatment (Clark et al., 2017). In contrast, CPD tends to progress at a slower rate. Despite their differences, both AgPD and CPD can present in more severe forms ultimately leading to tooth loss and edentulism (Brito et al., 2018). Although AgPD and CPD share several similarities, there are notable clinical differences between the two, including: (i) age of disease manifestation (i.e.detection), (ii) rate of disease progression, (iii) destructive patterns, (iv) indications of inflammation, and (v) plaque and calculus levels (Armitage and Cullinan, 2010). CPD is characterized by the gradual progression of the disease over time in the absence of appropriate treatment, while AgPD is characterized by rapid attachment loss and bone destruction (Cardoso et al., 2018).

The primary cause of periodontal inflammation is the microbial biofilms that form on the surface of teeth and expand to the gingival crevice (Larsen and Fiehn, 2017). Bacteria in these biofilms exploit their pathogenicity by causing damage to gingival tissue using direct and/or indirect mechanisms. Direct damage is caused by several bacterial factors that affect the cells and intercellular matrix of the host connective tissue. These bacterial factors generally involve secreted bioactive molecules, such as exoenzymes, toxins, and metabolic end-products (Siqueira and Rôças, 2024). Moreover, some somatic contents of bacteria, such as cell wall contents (peptidoglycan and lipoteichoic acid of Gram-positive bacteria and lipopolysaccharide (LPS) of Gram-negative bacteria), fimbriae, flagella, outer membrane proteins (OMPs), vesicles (OMVs), nucleic acids, and exopolysaccharides, are released into the adjacent tissues and stimulate the host immune mediators (Siqueira and Rôças, 2019). Table 1 is presents the virulence factors of common bacterial pathogens involved in PD. Bacterial components can trigger inflammatory and non-inflammatory host cells to express immunological factors and mediators, such as cytokines and prostaglandins. These mediators have a stimulating effect on bone tissue resorption, which is a characteristic feature observed in PD lesions (Lamont et al., 2020) ( Figure 1 ). The purulent exudate formed in acute apical abscesses is another example of indirect bacterial damage to gingival tissue. The host’s immune response to bacterial antigens originating from the root canal is considered the primary factor in the development of pus associated with abscesses (Karamifar et al., 2020). When periodontal tissues encounter bacterial cell-associated components known as pathogen-associated molecular patterns (PAMPs), certain host cell receptors referred as pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) recognize the pathogens and trigger the host immune response. TLRs are expressed on the surface of gingival epithelial cells, fibroblasts, dendritic cells (DCs), and macrophages (Becerra−Ruiz et al., 2022). PRRs including TLRs, are capable of recognizing conserved regions of PAMPs such as LPS, peptidoglycans, bacterial DNA, and lipoproteins (Li and Wu, 2021). TLRs play an essential role in triggering innate immunity. They are evolutionarily conserved and provide the first line of defense against microbial pathogens upon entry into host tissues (Kawai et al., 2024). Proinflammatory reactions induced by TLRs rely on the stimulation of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. These pathways coordinate the transcription and synthesis of proinflammatory mediators such as cytokines and chemokines (Collins et al., 2019). Thereafter, non-resident leukocytes, such as PMNs are attracted to the site of infection in response to specific cytokines and chemokines produced (Duan et al., 2022). PMNs are the most infiltrated leukocytes (50%-70%) and serves as an initial defense against the microbial pathogens in dental plaque. PMNs play a critical role in maintaining the healthy condition of periodontal tissue and provide the first-line mechanisms in the innate immune system. PMNs employ various specific mechanisms of action, including degranulation, chemotaxis, phagocytosis, formation of reactive oxygen species (ROSs), and the formation of neutrophil extracellular traps (NETs) (Sczepanik et al., 2020).

PMNs are central player in inflammation as they migrate to infected tissues to eliminate invading microorganisms. While PMNs in the gingival crevice can interact with bacterial biofilms on tooth surfaces, they are unable to completely eliminate the entire population of periodontal microorganisms (Alfakry et al., 2016). Whether there is an overabundance or a deficiency of activated PMNs, their role in causing periodontitis remains crucial (Hajishengallis et al., 2015). On the contrary, excessive activation of PMNs can lead to elevated levels of toxic substances and ROS, which characterize localized AgPD (Hasturk and Kantarci, 2015). ROS production can activate granular proteases, leading to the formation of NETs, which are networks composed of extracellular fibers of DNA that restrict invading microorganisms. Moreover, ROS can increase the permeability of bacterial membranes, causing damage to their DNA, proteins, and cell envelope. ROS formation serves as a potent antimicrobial defense mechanism and plays a crucial role in innate immunity against pathogens (Brings et al., 2020; Veenith et al., 2022).

In various types of PD, PMNs can either contribute to antimicrobial defense or tissue damage (Ramadan et al., 2020). PMNs also play a role in periodontal tissue damage by releasing degradative enzymes, such as matrix metalloproteinases (MMPs). MMPs are a class of enzymes responsible for breaking down the ECM contents, including collagen and elastin. In PD, the synthesis of MMPs is increased, primarily by immune cells and resident cells in the periodontal tissues. The overactivity of MMPs leads to the degradation of connective tissue fibers and contributes to alveolar bone loss in PD. PMNs can directly promote osteoclastic bone resorption by increasing the expression of membrane-bound receptor activator of nuclear factor-κB ligand (RANKL), a critical osteoclastogenic cytokine. PMNs also have the ability to release collagenase, which plays an essential role in bone resorption (Hajishengallis et al., 2016). However, PMNs typically do not express soluble RANKL (Chakravarti et al., 2009), and are only capable of mediating periodontal bone resorption when they are adjacent to the bone tissue. During inflammatory conditions, osteoclast progenitors respond to several mediators produced by induced CD4⁺ T cells including RANKL, TNF-α, and interleukins (IL)-17. Among CD4⁺ T cells, Th17 cells have been demonstrated to promote osteoclast differentiation. Th17 cells increase expression of IL-17 in inflammatory conditions, which is associated with increased bone destruction and osteoclastogenesis by upregulating RANK in osteoclast progenitors and increasing RANKL expression in osteoblasts (Madel et al., 2019). Osteoprotegerin (OPG) is a member of the TNF receptor superfamily, and acts as a soluble decoy receptor. It inhibits the interaction of RANKL with its functional receptor on osteoclast precursors (Liu and Zhang, 2015). The expression of RANKL and OPG may also be affected by amelogenin, which regulates odontoclast formation (Galler et al., 2021). A recent study showed that bone resorption is a common feature of PD. This process is intensified by increased RANKL expression and simultaneous downregulation of OPG, leading to an elevated RANKL/OPG ratio and subsequent activation of osteoclasts (Abdullameer and Abdulkareem, 2023).

Approximately one third of the variance observed in the frequency of periodontitis can be attributed to genetic factors. This heritability index has been consistent across different populations studied and tends to increase with the severity of PD (Nibali et al., 2019). Genetic factors play a role in regulating inflammatory responses within affected tissues and the damage induced in the alveolar bone (Tettamanti et al., 2017). Numerous scientific studies have investigated the influence of genes and their variants (polymorphisms) on host responses in periodontitis. Genetic polymorphisms can lead to changes in the encoded proteins or their expression, potentially altering innate and adaptive immune responses, and influencing disease outcomes. Interestingly, certain genetic polymorphisms may also provide protection against disease (Laine et al., 2012). Polymorphisms, defined as genetic variants occurring in at least 1% of a population, originate from mutations. Approximately 90% of polymorphisms are Single Nucleotide Polymorphisms (SNPs), in which a single nucleotide base is replaced by another. While most SNPs in genes do not alter the protein produced, they can still affect the gene’s function. Given that all forms of PD are associated with bacterial infections, it remains challenging to delineate the relative contributions of genetic and environmental factors to these complex disorders. Specific genetic polymorphisms, such as those in Interleukin-1 (IL-1), IL-6, IL-10, Fcγ receptors (FccR), Vitamin D receptor (VDR), and TNF-α genes, have been shown to be connected with periodontitis (Laine et al., 2012; Sayad et al., 2020). Similarly, polymorphisms in matrix metalloproteinase (MMP) genes may influence the expression or activity of MMPs, potentially increasing susceptibility to periodontal conditions (Li et al., 2016). Some studies have identified associations between the expression of RANKL/RANK/OPG triad elements and PD (Cochran, 2008). Although no genetic polymorphism in the RANKL/RANK/OPG triad genes has been confirmed as a risk factor for root resorption, further research is needed to explore this possibility. Studies have shown that overexpression of RANK in monocyte/macrophage lineage cells and gingival epithelial cells in mice led to decreased alveolar bone height and an increased number of TRAP-positive cells in the alveolar bone. This suggests excessive osteoclast activity and accelerated bone resorption, possibly due to inflammation in the gingival epithelium, which occurs prior to any detectable bone loss (Sojod et al., 2017).

Dental plaque, also known as microbial plaque, oral biofilm, or dental biofilm, is a complex and highly organized community of microorganisms. Biofilm forms on the surfaces of teeth and is embedded in a matrix of polymers from both host and bacterial origins. Oral biofilms play a crucial role in the development of a variety of diseases in the oral cavity and throat, including dental caries, PD, endodontic infections, tonsillitis, and alveolitis (Colombo et al., 2015). Biofilm formation begins with the initial adhesion of single free floating, planktonic cells to a surface (Sauer et al., 2022) ( Figure 2 ). Loose, long-range physicochemical interactions between the microbial cell surfaces and the pellicle-coated tooth enable reversible adhesion through van der Waals forces and hydrophobic interactions. This is followed by more robust and closer interactions between ligands on the surface of the early colonizers and matching receptors in the pellicle, ultimately leading to permanent attachment through their pili (see Figure 2 ). Thus, the acquired pellicle, largely derived from the host, actively guides the pattern of initial microbial colonization (Barnier et al., 2021; Darveau and Curtis, 2021). Bacterial biofilm is composed of bacteria that are enclosed in a polymeric matrix that they produce (Bîrluţiu et al., 2017). During this process, a self-generated matrix of extracellular polymeric substance (EPS) forms a tough barrier, shielding the bacteria from external stress (Das, 2022). The accumulation of small bacterial clusters and layers leads to the formation of plaque biofilm. In PD, mature biofilm is characterized by matrix macromolecules such as extracellular DNA (exDNA). This exDNA exists in two forms within the matrix: free DNA and extracellular DNA traps (ETs). Regardless of its origin, exDNA is essential for initiating biofilm formation and maintaining its three-dimensional structure (Wei et al., 2024). Microbial communities within the biofilm engage in a series of physical, metabolic, and molecular interactions that can influence antibiotic resistance and pathogenicity. Studies have shown that microbial cells embedded in the biofilm are 10–1000 times more resistant to antibiotics compared to planktonic cells (Digel et al., 2020). Bacterial attachment to biomaterial surfaces involves a variety of physicochemical interactions and biological processes, with mechanisms that are specific to either the bacteria or the substrate (Kreve and Dos Reis, 2021). When saliva contacts the teeth, proteins from the saliva stick to the tooth surface, creating an acquired salivary pellicle. This pellicle covers all tooth surfaces in the mouth and serves as a link between the dental hard tissue and the oral environment (Chawhuaveang et al., 2021). The pellicle is primarily composed of proteins, amino acids, fatty acids, glycoproteins, carbohydrates, lipids, and other compounds present in saliva. It also contains microorganisms like bacteria and fungi. This layer acts as a lubricant and provides protective properties for the teeth (Enax et al., 2023). The attachment of bacteria to the surfaces of teeth during dental plaque formation occurs through a hydrophobic interaction. This interaction involves a phenylalanine side chain of bacterial surface molecules and a leucine side chain of a salivary glycoprotein in the formed pellicle. Additionally, calcium bridging (takes place, which is the results of an electrostatic attraction) between a negatively charged carboxyl group of a bacterial protein and a positively charged calcium ion.

Furthermore, dietary sucrose is transformed by bacterial glucosyltransferase into glucan. Glucan contains multiple functional residues that can interact with amino acid side chains like serine, tyrosine, and threonine. Bacterial fimbriae play a role in providing the terminal adhesin portion necessary to bind to a sugar component of a salivary glycoprotein in the acquired pellicle (Digel et al., 2020).

Streptococci compete for adhesion sites on the saliva-covered surface of teeth and can produce antimicrobial substances. S. mutans can dominate oral biofilms, leading to the development of dental caries (Moschioni et al., 2010). S. mutans is the primary early colonizing bacteria responsible for dental caries because of its ability to recognize salivary pellicle receptors. S. mutans antigen I/II (Ag I/II) is a key factor in this process, playing a vital role in adhering to the tooth surface and in microbial co-aggregation during the initial stages of biofilm formation (Rivera-Quiroga et al., 2020). Oral bacteria that are unable to adhere to surfaces are carried into the digestive system through salivary flow. However, many oral bacteria have developed mechanisms to attach to solid surfaces including teeth covered with salivary films or other bacteria already attached to these surfaces (co-aggregation), as well as epithelial layers (Kolenbrander et al., 2010). In addition to Ag I/II (also known as SpaP, Pac, P1), S. mutans also produces glycosyltransferases (Gtfs), various glucan-binding proteins (Gbps), and collagen-binding proteins, which play a role in coordinating the plaque formation (Matsumoto-Nakano, 2018). S. mutans biofilm formation is a complex process involving interactions between proteins and bacteria. It begins with the adhesion of a single cell, followed by accumulation, microcolony formation, and eventually developing into a mature biofilm (Krzyściak et al., 2014). Adherence to host tissues is a crucial step in the pathogenic process, typically facilitated by bacterial surface-exposed proteins. In S. mutans, adhesion mechanisms include both sucrose-dependent (requiring Gtfs) and Ag I/II -dependent pathways (Scharnow et al., 2019).

Without sucrose, S. mutans produces key adhesins like Ag I/II, which specifically attach to a glycoprotein known as salivary agglutinin (SAG) (Lamont et al., 1991; Mitchell, 2003). It has been suggested that this also plays a role in bacterial adhesion to teeth (Jakubovics et al., 2005), and biofilm formation. Various oral bacteria have the LuxS/AI-2 quorum sensing (QS) system. LuxS contributes to biofilm formation, regulates acid and oxidative stress tolerance, and controls the production of the lantibiotic mutacin I. Additionally, AI-2-like signaling molecules can influence carbohydrate metabolism and biofilm matrix composition (Wang et al., 2017).

It is crucial to highlight that PD seems to be initiated by a relatively small group of periodontal pathogens within the intricate dental biofilm (Popova et al., 2013). The currently identified periodontal pathogens constitute only a small fraction of the approximately 600 bacterial species that can colonize dental surfaces both above and below the gingival margin, as well as the oral mucous membranes. Clinical and experimental evidence confirm that certain bacterial strains in the periodontal environment can cause inflammation of the gingival tissue and lead to bone destruction. These strains are known as periodontal pathogens (Paster et al., 2006). Over the past three decades, there has become widely believed that PD is polymicrobial infections (Armitage, 2004; Taba et al., 2005). Only a small percentage of the bacteria in dental biofilm are considered pathogenic for periodontal tissues. It is well established that the majority of periodontal pathogens are anaerobes. However, the biofilm can also contain facultative aerobes, capnophiles, and microaerophiles. Their numbers vary based on the conditions within the established biofilm and periodontal pocket. Most periodontal pathogens are the primary agents responsible for actual PD. Certain bacterial species in the periodontal environment, such as Actinomyces, Streptococcus, and Staphylococcus spp., which are part of the commensal flora, can cause opportunistic infections if the ecosystem is disturbed. Detection of Enterobacteria, viruses, and Saccharomyces spp. in periodontal pockets may indicate a superinfection linked to a destructive periodontal process. Some studies have focused on identifying the subgingival flora most characteristic of specific PD. While findings have linked certain periodonto-pathogens to specific periodontal conditions, there is still no definitive evidence that particular bacterial species are unique to different types of PD. Even in small amounts, these bacteria can cause damage to periodontal structures (Socransky et al., 1998; Mombelli et al., 2002).

Microorganisms can cause disease directly by invading host tissues or indirectly through bacterial factors and toxins. In order to be considered a pathogen associated with PD, a microorganism must possess several key characteristics including:

Studies on endodontic-periodontic bacteria commonly refer to the six complexes initially described by Socranski et al. These complexes are color-coded as blue, green, yellow, purple, orange, and red (Socransky et al., 1998) ( Figure 3 ). The red complex bacteria are commonly linked to PD and are often found together in dental plaque, especially in deeper areas near to the epithelial layers of the periodontal pocket. This is largely due to interactions, co-aggregation, and metabolic dependencies among these three bacterial species (Nayak et al., 2018).

The presence of the red complex is closely linked to advanced periodontal lesions, which are characterized by deeper pockets and bleeding (Silva and Cascales, 2021). Additionally, the prevalence and quantity of the red complex increase as the depth of these pockets increases (Mohanty et al., 2019). Next-generation sequencing (NGS) technologies have revealed a wider range of diversity within the oral microbiome and have shown an intricate relationship between microbiome composition and periodontal disease states. This includes a correlation between increased microbial diversity and pocket depth. Recent studies have discovered new microbial connections with PD, emphasizing genera such as Schwartzia and Aerococcus as linked to the condition. These findings indicate that the microbial environment of PD is more intricate than previously believed (Sisk-Hackworth et al., 2021). A recently identified bacterium from the Bacteriodetes phylum, known as Candidatus Bacteroides periocalifornicus (CBP), has been discovered in dental plaque and shows a strong association with the pathogenic “red complex” found in deep periodontal pockets. CBP is commonly found in the oral cavities of both healthy and diseased individuals but is not detected in gut or skin samples. The abundance of CBP increases with pocket depth and it coexists with F. nucleatum, T. denticola, and P. gingivalis. Its presence is closely linked to members of the red complex rather than healthy commensals, suggesting that CBP could be a new candidate addition to the symbiotic and pathogenic red complex (Torres et al., 2019).

The blue, yellow, green, and purple complexes consist of bacterial species typically associated with a healthy periodontal environment (Carrouel et al., 2016).

Despite the significant focus on the composition of the human microbiome in recent years, the exact mechanisms by which these microbial communities influence disease and maintain health remain largely unknown. Nonetheless, recent studies have revealed that several chronic conditions affecting the mouth and gastrointestinal tract are linked to changes in the microbiome, known as “dysbiosis.” Dysbiosis refers to a harmful shift in the relative abundances and individual components of the microbiome, which vary during healthy states. This shift leads to major dysbiosis-related diseases in humans, including periodontitis, irritable bowel syndrome, chronic vaginosis, and others. Among these, periodontal disease is a prominent dysbiotic condition due to the diverse genera present in both healthy and periodontal microbiomes (Sudhakara et al., 2018).

Oral microbial dysbiosis is a significant factor in the development of oral diseases, including dental caries and periodontal conditions (Hajishengallis, 2015).

This parasitic or pathogenic state, where microbes cause disease in the host, is known as “dysbiosis “or an “unbalanced microbiome” Inflammation plays a key role in altering the microbial community, leading to a continuous cycle of dysbiosis, immune response, and tissue breakdown. The environmental conditions within inflamed periodontal pockets—such as low oxygen levels, enriched nutrients from host protein breakdown, and increased gingival fluid volume—along with synergistic microbial interactions, create a favorable environment for inflammophilic, anaerobic, proteolytic, and fastidious organisms (Kawamoto et al., 2021).

According to Peterson et al., dysbiosis can be identified through three distinct, yet not mutually exclusive, scenarios that may occur simultaneously: i) a general loss of microbial diversity; ii) the loss of beneficial microbes; and iii) the expansion of pathogenic microbes (Petersen and Round, 2014; Van Dyke et al., 2020) These changes provoke an exaggerated inflammatory response in the host via virulence factors, resulting in tissue destruction (Hajishengallis and Lamont, 2012).

In addition to bacteria, the oral mucosal tissues also harbor to various other microorganisms, including archaea, fungi, and viruses. However, research on the relationship between PD and systemic diseases tends to focus primarily on the bacterial component of the microbiome (Unniachan et al., 2020). Candida albicans is the predominant fungal species observed in both healthy and infected oral cavities, accounting for over 80% of oral fungal isolates (Talapko et al., 2021). It continues to be the leading fungal pathogen identified in individuals with PD (Jabri et al., 2021). Studies have shown that C. albicans can promote the invasion of P. gingivalis into human gingival epithelial and fibroblast cells in vitro (Tamai et al., 2011). This indicates that C.albicans may contribute to the development or worsening of periodontal disease. The hyphal-specific adhesin Als3, found on the surface of the fungal, is believed be essential for its interaction with P. gingivalis. Additionally, pretreating gingival epithelial cells and fibroblasts with C. albicans has been demonstrated to increase the invasion of P. gingivalis (Montelongo-Jauregui and Lopez-Ribot, 2018). Previous research has investigated the role of Candida species in dental caries, revealing that C. albicans significantly contributes to biofilm formation and accumulation (Falsetta et al., 2014; Sztajer et al., 2014). A synergistic relationship between C. albicans and oral bacteria enhances the virulence of polymicrobial biofilms, thereby increasing the resistance of fungal cells to antimicrobial agents and environmental stresses (Bartnicka et al., 2019). Specifically in the context of periodontitis, oxygen consumption by C. albicans appears to create an oxygen-deficient environment that facilitates the growth of P. gingivalis and promotes its ability to invade host cells (Jabri et al., 2022). The pathogenicity of C. albicans is linked to its ability to adhere to various surfaces, form hyphae, produce hydrolytic enzymes, invade host tissues, and trigger inflammatory responses (Cavalcanti et al., 2016).

Viruses are recognized as important contributors to the onset and progression of periodontitis. Among them, herpesviruses—including herpes simplex virus-1 (HSV-1), Epstein–Barr virus (EBV), and cytomegalovirus (CMV)—either individually or in combination with other subgingival pathogens, play a pivotal role in both the initiation and progression of the disease (Abooj and Varma, 2021). Herpesvirus infections have the potential to promote the proliferation of bacterial pathogens within periodontal tissues. Macrophages infected with cytomegalovirus or Epstein–Barr virus exhibit a diminished immune response when confronted with periodontal bacteria. Furthermore, proteins produced by herpesviruses on the surface of infected cells can create new binding sites that facilitate the attachment and growth of periodontopathic bacteria (Slots, 2015).

Within the oral microbiome, archaea represent a minor fraction, predominantly consisting of methanogenic phylotypes—strict anaerobes that produce methane. Notable species include Methanobrevibacter massiliense (M. massiliense), Methanobrevibacter smithii (M. smithii), and Methanobrevibacter oralis (M. oralis), which have been linked to periodontitis (Mosaddad et al., 2019; Pilliol et al., 2024). Methanogens have been identified in subgingival samples collected from patients suffering from periodontitis, peri-implantitis, and infected root canals. They have also been detected in saliva specimens from these individuals (Sogodogo et al., 2019). M. oralis is the most common archaeal phylotype found in the subgingival biofilm of both healthy individuals and those with aggressive periodontitis, indicating that it may be a regular component of the oral microbiota. While Archaea are generally less abundant and diverse in subgingival regions, the higher levels of methanogens seen in individuals with generalized aggressive periodontitis (GAgP) compared to periodontally healthy (PH) individuals suggest their role in the ecological changes of the microbiota associated with aggressive periodontitis (Matarazzo et al., 2011).

The successful treatment of an infection relies on accurately diagnosing of the pathogens contributing to its etiopathogenesis. Diagnosing an infection can be challenging, especially in patients with a polymicrobial infection in organs are naturally colonized by bacteria, like the skin, gastrointestinal tract and oral cavity. Methodological problems in detecting the complex subgingival microbial population, which is heavily colonized by numerous species of strict and facultative anaerobes and fastidious bacteria, have significantly hindered the accurate diagnosis and antibiotic therapy of PD (Socransky and Haffajee, 1994). The treatment of PD should be started as soon as possible. Mild to moderate cases of PD are typically treated using nonsurgical procedures, such as supplementary antimicrobial agents, dental scaling, and root planning (Slots, 2012; Albandar, 2014). Nonsurgical treatments are typically not enough for sever PD. Surgical procedures are necessary to reduce pocket depth and establish anatomical contours at the periodontal junction (Yang et al., 2021). Systemic antimicrobial drugs are administered as monotherapy or in combination therapy. However, it is highly recommended to combine antibiotics with non-surgical periodontal therapy to achieve optimal clinical outcomes (Souza et al., 2020). The most common antibiotic regimens for PD include β-lactams, tetracyclines, quinolones and metronidazole (Keestra et al., 2015). The combination of metronidazole and amoxicillin is the most frequently used antimicrobial therapy for PD (Elashiry et al., 2021). This combination has been shown to have synergic effects, reducing the necessary levels of both antibiotics for biological effects (Mugri, 2022). A 7-day regimen of 500/500 mg or 500/400 mg of amoxicillin and metronidazole is recommended for PD (McGowan et al., 2018).

Azithromycin is a macrolide agent generally administer as an alternative in case of penicillin-allergy. The suggested regimen for azithromycin is 500 mg/day for 3 days and it an assists in non-surgical procedures and mechanical plaque elimination in the treatment of PD (Jones and Hoyle, 2022). Macrolides should not be combine with clindamycin, due to their similar cellular target and antagonistic effects (Flynn, 2019).

Clindamycin is a lincosamide agent that has a bacteriostatic effect on anaerobic bacteria and is highly effective against mixed infections caused by both anaerobic and aerobic bacteria. It has favorable pharmacokinetics and has become a commonly prescribed alternative for oral infections in patients with penicillin allergy. The common oral dosage of clindamycin is 300 mg every 6 h (Jeske, 2024). Clindamycin is the only antimicrobial drug that reduces the attachment of bacteria to epithelial cells on the mucosal surface by decreasing the expression of microbial factors. It also decreases the production of proinflammatory cytokines, such as TNF-α and IL-1β, which can lead to additional destruction of periodontal tissues, when overexpressed by microorganisms and neighboring cells. Therefore, the decreased release of TNF-α and chemokine CXCL-1 are additional effects of clindamycin, which help to suppress the inflammatory condition such as PD (Luchian et al., 2021).

Tetracycline derivatives are generally administer as supportive agents in PD antimicrobial therapy (Mohammad et al., 2022). Tetracycline has a long shelf-life, which preserve its antibacterial effects for an extended period, and is slowly released from the tooth surface (Kafle et al., 2018).

Tetracycline also possesses a surprising capacity to prevent host-derived MMP effects and connective tissue damage decreases the release of inflammatory mediators, and lead to the concept of host-modulation therapy in the treatment of PD. Upregulated collagen synthesis, osteoblast activity, and bone formation are non-antimicrobial properties of tetracycline, making it an appropriate option for PD treatment (Golub and Lee, 2020).

Ciprofloxacin is a broad-spectrum antibiotic that is effective against various pathogens -associated PD, including A. actinomycetemcomitans. It efficiently penetrated the infected periodontal tissues and can reach higher levels in the crevicular fluid compared to the blood.

Because periodontal infections are commonly polymicrobial and caused by a variety of periodontal pathogens, a combination of antibiotics is often used to treat AgPD (Bidault et al., 2007).

Moxifloxacin, another quinolone, has shown significant antimicrobial effects on PD-associated pathogens in vitro and in a clinical study involving AgPD cases. It has been shown that daily 400 mg of moxifloxacin, used in conjunction with one-stage full-mouth cleaning and root planning improved clinical outcomes compared to mechanical treatment alone in AgPD cases (Ardila et al., 2015). However, moxifloxacin is not typically administered as the first-line drug due to its high cost, and is usually reserved for case where first-line antimicrobials and surgical procedures have been unsuccessful (Holmes and Pellecchia, 2016).

Understanding the role of oral microbiota dysbiosis in the initiation and progression of PD is crucial for devising effective therapeutic strategies aimed at reducing bacterial load and restoring microbiological balance (Sachelarie et al., 2025). Conventional treatments for periodontitis often don’t completely eliminate harmful pathogens (Matsubara et al., 2016). However, when executed meticulously, these treatments can promote a healthier oral environment by modifying the composition and population of the microbial community and aiding in the maturation of the host immune response (Fragkioudakis et al., 2021). The primary methods for treating periodontitis include controlling biofilms, mechanically removing plaque, and using antibiotic therapy (Slots, 2017). In recent years, the main goal of these treatments has evolved to focus on restoring homeostasis within the oral microbiota. However, bacterial strains involved in PDs are increasingly becoming resistant to antibiotics, posing a significant challenge to conventional treatments (Haque et al., 2022). Consequently, there has been a growing focus on complementary approaches to enhance traditional mechanical treatments. Among these, probiotics have gained attention from researchers and clinicians for their potential to help restore microbial balance. Probiotics produce compounds such as lactic acid, hydrogen peroxide, and bacteriocins, which can reduce pathogenic bacterial biofilms and decrease levels of pro-inflammatory factors like cytokines, collagenases, elastases, and prostaglandin E2. These probiotic bacteria then adhere more firmly to the oral cavity’s surface, preventing new pathogens from colonizing. Through this process, bacterial aggregation and co-aggregation occur, leading to a new microbial balance that forms a healthy biofilm (Mishra et al., 2020). The incorporation of probiotics in periodontal treatment represents a promising innovation with the potential to significantly enhance long-term clinical results. While phage therapy has demonstrated efficacy against numerous infections, its application in the treatment of oral diseases remains underexplored.

Bacteriophage therapy offers a novel and promising alternative method of treatment (Shlezinger et al., 2017). Bacteriophages, also known as phages, are viruses that infect bacteria by entering the host cell and initiating a cycle of phage production. They play a crucial role in the infectious cycle of lytic phages, ultimately leading to the lysis or death of the bacterial host (Zhu et al., 2025). Phages, which are highly selective, non-toxic, self-replicating, and capable of infiltrating biofilms, offer a novel alternative to traditional biofilm prevention techniques (Szafrański et al., 2017). Their ability to combat dental plaque is highlighted by their small size, allowing them to penetrate biofilm layers with high efficiency. Phage therapy could become a crucial treatment option for root canal infections that are resistant to conventional endodontic methods and has shown effectiveness against root canal infections caused by Enterococcus faecalis, a foodborne pathogen associated with various diseases and potentially implicated in periodontal health (Łasica et al., 2024; Hosseini Hooshiar et al., 2024).

Over the past century, lasers have been used to treat variety of diseases, including periodontitis. A laser device generates electromagnetic radiation at a specific wavelength and a low-intensity beam, which has significant effects on tissues. The use of lasers is considered beneficial for treating a range of infectious and inflammatory conditions (Isola et al., 2021). Several studies have shown that lasers can promote periodontal wound healing and regeneration by effectively removing and decontaminating diseased tissues, as well as by modulating or activating cell metabolism in the surrounding tissues. In the past decade, low-intensity diode lasers have been used in combination with photosensitizers to activate topical photosensitizing agents such as antimicrobial photodynamic therapy (aPDT), to help reduce or eliminate periodontopathogen bacteria as a complement to mechanical debridement in patients with periodontitis (Chambrone et al., 2018). Photodynamic therapy (PDT) is a non-thermal photochemical reaction that requires the simultaneous presence of visible light, oxygen, and a dye or photosensitizer (PS). Various PS have been studied for their ability to bind to bacteria and effectively produce reactive oxygen species (ROS) when exposed to light. These ROS are generated through type I or II mechanisms and can deactivate various types of bacterial cells (Sperandio F et al., 2013). The most common laser applications for periodontal therapy include diode, carbon dioxide (CO2), and neodymium-doped lasers. These wavelengths can be used in conjunction with mechanical non-surgical instrumentation to debride connective tissue and epithelium within periodontal pockets, inactivate bacteria, and ablate subgingival calculus (Salvi et al., 2020).

Various local and systemic approaches have been employed to effectively treat periodontitis. Currently, controlled local drug delivery is more favored compared to systemic methods. This is because it focuses on enhancing therapeutic outcomes by achieving factors such as site-specific delivery, low dose requirements, bypassing first-pass metabolism, reducing gastrointestinal side effects, and decreasing dosing frequency (Joshi et al., 2016). Selecting the right antimicrobial agent with the appropriate route of administration is crucial for successful periodontal therapy. Local drug delivery systems (LDDS) such as irrigating systems, fibers, gels, strips, films, microparticles, nanoparticles, and low-dose antimicrobial agents are available to deliver antimicrobial agents to sub-gingival diseased sites with minimal or no side effects on other body sites (Rajeshwari et al., 2019).

Several studies have revealed that levels of resistance to certain antibiotics increased have in microbial agents involved PD. The most significant factor contributing to the rise in antimicrobial resistance is the misuse or overuse of these agents. Resistance to metronidazole in PD- associated pathogens has been reported in several studies (Mínguez et al., 2019). Higher levels of metronidazole resistance have been reported in A. actinomycetemcomitans compared to P. gingivalis. The resistance frequency of P. gingivalis strains from Colombia to amoxicillin, azithromycin, and metronidazole has been reported as 24.6%, 21.3% and 24.6%, respectively (Ardila and Bedoya-García, 2020). However, some studies have described the sensitivity of all P. gingivalis strains to all or most tested antimicrobial agents (Mínguez et al., 2019; Rams et al., 2023).

Some β-lactamase-producing pathogens may contribute to refractory PD. Since PDs commonly are polymicrobial, the presence of β-lactamase-producing pathogens may prevent nonproducing organisms in subgingival plaques from being affected by β-lactam agents, leading to treatment failure or disease recurrence (Handal et al., 2004). A significant increase in resistance to clindamycin and amoxicillin has been reported over a 20-year period among P. gingivalis isolated from severe PD patients in the United States (Rams et al., 2023).

Choosing the appropriate antibiotics for PD is a complex and challenging due to the presence of over 700 bacterial species in the oral cavity (Radaic and Kapila, 2021). On the other hand, selecting an antimicrobial agent for PD treatment based on microbiological analysis and antibiotic susceptibility pattern is practically impossible. There are few guidelines on how to determine and interpret antimicrobial resistance patterns of anaerobic oral bacteria because there is inadequate information on the relationship between minimal inhibitory concentrations (MIC) of antibiotics, actual local (oral) levels in vivo (PK/PD data) and clinical outcomes (Jepsen et al., 2021). On the other hand, most of the bacteria that cause PD are fastidious, requiring complex culture media and nutritional supplements for in vitro growth, as well as a long incubation period.

It is well known that antibiotic resistance varies between countries based on their usage patterns and levels of antibiotic administration in general clinical settings (Van Winkelhoff et al., 2005). Antimicrobial drugs are prescribed empirically based on the periodic antibiotic sensitivity patterns reported by national researches (Luan et al., 2023). Undoubtedly, prospective clinical and surveillance studies, as well as monitoring the resistance levels to antibiotics will be effective in the optimal usage of antibiotics and control of drug-resistant strains.

The microbial-biofilm formation and dental plaque is the initial stage of PD. The extended presence of plaque on the teeth’s surface causes it to migrate into the surrounding periodontal tissues. This spread triggers the infiltration of host immune cells, leading to inflammation of the gingival tissue and ultimately bone destruction. The damage and injuries caused by PD result from immune system mediators and virulence factors produced by pathogenic bacteria. These effects are primarily due to interactions, co-aggregation, and metabolic dependencies among the pathogens. Therefore, prevention of dental plaques and antimicrobial therapy can have a significant impact on prevention and treatment of PD. The prospective clinical and surveillance studies, as well as monitoring the resistance levels to antibiotics will be effective in the optimal usage of antibiotics and control of drug-resistant pathogens caused PD. Novel approaches like NGS and OMICS-based methods can be used to more accurately study the microbiology and pathology of PD. Understanding the role and effects of bacterial secondary metabolites, such as short-chain fatty acids, produced by the microbiome in the prognosis and pathogenesis of PD provides valuable data the prevention and the development of new therapeutic and diagnostic methods. Because PD is polymicrobial and there is increasing antibiotic resistance among its pathogens, there is an urgent need to update laboratory and clinical guidelines and assess precise and reliable methods for detecting resistant strains.