The human oral cavity contains a complex community of microorganisms (including oral pathogens) that exert a substantial influence on dental and systemic health. Various microbial niches appear in the tissues of the human oral cavity owing to factors such as nutritional content, pH, oxygen concentration, and metabolic properties of the microbial ecosystem1-3). Biofilm formation in the oral environment is a critical mechanism for these oral pathogens. While biofilms naturally occur in healthy teeth, the accumulation of successive dental biofilms can play a critical role in the development of diseases, such as dental caries, gingivitis, and periodontitis4,5). Furthermore, bacteria from dental biofilms may cause systemic diseases such as endocarditis, diabetes mellitus, atherosclerosis, rheumatoid arthritis, and orodigestive cancer through bacteremia or indirect manners6-10). Research on oral pathogens is important to understand their roles in various systemic diseases and conditions. Poor oral hygiene and periodontal health can affect systemic health and vice versa11). Understanding the relationship between oral pathogens and systemic diseases can improve diagnosis, prevention, and treatment strategies. Therefore, research on oral pathogens is crucial to improve overall oral and systemic health outcomes.
Oral biofilms are formed in several stages and involve various bacteria. Saccharolytic bacteria, such as
Additionally, other species and types of oral pathogens live in the human oral cavity. For example,
These bacteria rapidly colonize various surfaces within the oral tissue despite the turbulent environment within the human oral cavity. Colonization begins within several minutes and extensive microbial deposition occurs within a few hours. Biofilm development in the oral cavity can be divided into adhesion/coaggregation, microbial interactions, and extracellular matrix formation stages25,26).
Representative Examples of Participating Bacteria throughout the Oral Biofilm Formation Stages
Adhesion/coaggregation | Interaction | Matrix production | |||||
---|---|---|---|---|---|---|---|
Pathogen | Description | Pathogen | Description | Pathogen | Description | ||
Streptococci | AgI/II proteins result in aggregation | Early colonizing streptococci | Produce acids from sugars | Produce insoluble glucans, an important component of biofilm matrix | |||
Bindto pre-existing |
Utilize lactate produced by streptococci | Forma structural biofilm scaffold with proteins and extracellular DNA | |||||
Coaggregate with almost all other oral bacteria | Participate in numerous mutualistic interactions |
This review introduces the recent studies on the various pathogenic mechanisms of oral pathogens. Specifically, we describe the direct interactions between pathogens, quorum sensing signaling, and metabolite exchange that occur during biofilm formation by oral pathogens. We also summarized the virulence factors involved in biofilm formation by oral pathogens. These newly identified mechanisms of pathogenic virulence factors may provide new drug targets for the development of novel antibiotics against oral pathogens. Furthermore, we suggested methods for selective drug development against specific oral pathogens through a sequence comparison of drug target proteins that have not been previously introduced. Additionally, we present the possibility of discovering new antibacterial substances in marine organisms based on recent successful findings.
A literature search was performed using PubMed (https://pubmed.ncbi.nlm.nih.gov/) and Google Scholar (https://scholar.google.com/) databases. The Basic Local Alignment Search Tool (BLAST) was used to identify homologous protein sequences in other species.
Sixteen well-known drug target proteins for general pathogens were selected through a literature review using PubMed and Google Scholar. The sequences of these 16 proteins from the pathogen
Antibiotics prescribed for oral health are commonly used in dentistry for periodontal infections, non-periodontal infections, localized infections, focal infections, and as preventive measures during dental procedures. Antibiotic treatment involves direct application at the site of infection or systemic administration via ingestion. It is crucial to choose an appropriate approach by targeting antibiotic therapy specifically for oral pathogens, while preserving beneficial oral commensal bacteria, thereby inhibiting the growth of oral pathogens30,31).
Overuse and misuse of antibiotics in odontogenic infections can promote the colonization of resistant bacteria, and antibiotic-resistant gene-containing plasmids can spread across a broad niche of bacteria through transmission30,31). The emergence of multidrug-resistant oral pathogens that render conventional treatments ineffective has become a critical global health concern since conventional treatments become ineffective32). The development of novel antimicrobial agents is crucial owing to the increasing threat of multidrug-resistant oral pathogens and limited options for therapy33,34). Therefore, it is important to identify valuable sources of antibiotics in natural ecosystems35-37).
Marine organisms are rich sources of antibiotics. Marine sponges, such as those from the phylum Porifera, produce bioactive compounds that can be used to improve human health38). Natural compounds derived from marine microorganisms (including bacteria, fungi, actinomycetes, and cyanobacteria) exhibit promising antimicrobial properties and can act against various antibiotic-resistant pathogenic strains. Antibiotics produced by bacteria living in marine environments have also been studied; diverse metabolites have been isolated and their chemical structures elucidated39). Actinomycetes (specifically, marine actinomycetes) have been identified as potential producers of novel antibiotics, with strains such as
Antimicrobial Substances against Oral Pathogens Derived from Marine Organisms
Natural compound | Source | Description | Reference |
---|---|---|---|
Fucoidan | ∙Long chain sulfated and fucose-rich polysaccharide. | 43∼46 | |
∙Broad pharmacological effects include antibacterial, antiviral, and anti-inflammatory effects. | |||
∙Antimicrobial activity against |
|||
Halistanol sulfate | ∙Inhibition of biofilm formation and reduction of biofilm-associated gene expression in |
47, 48 | |
Mayamycin | ∙Inhibitory effect against |
49 | |
Salinisporamycin | ∙Inhibition of adenocarcinoma cell growth. | 50 | |
∙Antimicrobial activity against |
|||
Fridamycin A/D | ∙Antibacterial activity against multidrug-resistant |
51 | |
Callinectin | ∙Antibacterial activity against Gram-negative bacteria. | 53 | |
Coumarin | Diverse group of algae, marine fungi,and ascidians | ∙Inhibition of biofilm formation of |
54, 55 |
Biologically active compounds have been identified in several brown algae species. Fucoidan is a long chain, sulfated, fucose-rich polysaccharide found in the cell walls of brown macroalgal species, including
Microbial symbionts in marine sponges and corals produce bioactive compounds with antimicrobial properties. Halistanol sulfate, discovered in the sponge
Potential antibiotic candidates are found not only in bacteria but also in various marine organisms. For example, blue crabs (
Recent studies have shown that oral microorganisms coexist and balance the oral environment of a healthy person. When the oral environment deteriorates, the composition and ratio of oral microorganisms change, and pathogenic microorganisms increase59-61). Many oral pathogenic microorganisms are anaerobic, whereas commensal non-pathogenic oral microorganisms are often aerobic bacteria62,63). An attempt has been made to develop a drug specific to oral pathogens using the difference in energy metabolism pathways between aerobic and anaerobic microorganisms by developing an inhibitor of a characteristic enzyme only present in anaerobic microorganisms. For example, treatment with amixicile (an inhibitor targeting pyruvate:ferredoxin oxidoreductase) inhibits oral pathogen growth, whereas aerobic oral bacteria are unaffected64,65). Additionally, it is possible to develop a specific drug targeting oral pathogenic microorganisms because the amino acid sequences of drug target proteins differ between oral pathogenic and non-pathogenic oral microorganisms66,67). For example, there is a large sequence difference between peptide deformylases in
Amino Acid Sequence Differences of Drug Development Target Protein in Various Oral Bacteria
Possible drug target protein in |
Sequence identity/homology (UniProtKB code) with homologous protein | ||||
---|---|---|---|---|---|
Methionine-tRNA ligase (Q7MXK7) | 35.29%/53.07% (A0A829BNI5) |
34.14%/52.15% (Q8RE57) |
34.13%/52.38% (Q837B3) |
36.38%/55.29% (Q9K1Q0) |
37.32%/53.09% (J7SIB3) |
Peptide deformylase (Q7MT07) | 29.36%/45.96% (Q8DWC2) |
39.41%/60.10% (Q8REF0) |
30.80%/44.64% (Q82ZJ0) |
37.13%/53.96% (P63916) |
28.28%/43.85% (J7TGU5) |
Methionine Aminopeptidase (A0A134DR99) | 38.89%/54.25% (Q8DT38) |
47.08%/66.42% (A0A0X3Y2E4) |
41.94%/58.78% (A0A3N3SAK1) |
43.17%/61.15% (A0A0H5QGA8) |
37.99%/54.22% (J7TU94) |
Beta-ketoacyl-[acyl-carrier-protein] synthase III (Q7MAV3) | 38.53%/60.91% (Q8DSN2) |
43.63%/59.49% (Q8RGX7) |
38.04%/54.08% (Q820T1) |
39.83%/57.66% (Q9JXR6) |
40.51%/59.21% (J7SIA1) |
DNA gyrase subunit A (Q8L3L7) | 47.77%/67.08% (A0A0E3VYF0) |
47.53%/67.15% (A0A0M4SCH3) |
49.72%/69.97% (A0A1J6YID4) |
44.82%/62.87% (A0A076U4V3) |
48.54%/68.61% (A0A6N2YRL6) |
DNA gyrase subunit B (A0A134DMA2) | 55.57%/71.92% (A0A829BP53) |
53.77%/70.61% (A0A101K4X9) |
56.05%/70.85% (Q839Z1) |
40.93%/55.13% (A0A0H5QAZ0) |
56.33%/72.58% (A0A7L6WLW5) |
DNA topoisomerase IV subunit A (A0A2D2N546) | 27.48%/43.98% (A0A829BMX9) |
N/A | 28.63%/45.78% (Q93HU6) |
28.35%/43.60% (A0A0H5QAL8) |
29.65%/45.79% (J7TQR1) |
DnaK (P0C937) | 60.73%/72.36% (O06942) |
60.00%/71.82% (Q8RH05) |
60.78%/73.45% (Q835R7) |
60.39%/73.69% (Q9K0N4) |
61.40%/73.10% (J7TPQ1) |
Peptidoglycan glycosyltransferase (A0A2D2NAU4) | 27.65%/40.93% (A0A829BJP3) |
26.50%/44.43% (A0A133P5Z8) |
26.62%/40.80% (Q9EXN1) |
29.61%/44.90% (A9M1V1) |
27.81%/40.92% (J7TPX1) |
1-Deoxy-D-xylulose-5-phosphate reductoisomerase (Q7MUW3) | N/A | 42.11%/62.44% (Q8R622) |
N/A | 45.15%/63.35% (Q9K1G8) |
N/A |
Superoxide dismutase [Mn/Fe] (P19665) | 41.59%/54.67% (P09738) |
N/A | 45.41%/57.49% (Q838I4) |
N/A | 41.63%/54.55% (A0A0A1DUC0) |
Aspartate semialdehyde dehydrogenase (A0A2D2N2E1) | 46.60%/61.52% (P10539) |
30.81%/46.70% (A0A3P1VYK2) |
45.95%/62.16% (A0A2S7M0C8) |
32.93%/49.39% (P30903) |
44.33%/61.34% (J7TZ02) |
Methylenetetrahydrofolate dehydrogenase/cyclohydrolase (Q7MVE9) | 47.40%/64.29% (Q8DVC1) |
40.51%/61.41% (Q8RDM4) |
46.36%/68.21% (Q836W7) |
47.27%/63.02% (P0C277) |
45.37%/63.58% (J7TX79) |
Riboflavin biosynthesis protein (Q7MWK9) | N/A | 53.10%/68.57% (A0A101K6I4) |
51.43%/66.90% (R3HR06) |
N/A | N/A |
Lumazine synthase (Q7MUR5) | N/A | 41.32%/60.48% (Q8RIR4) |
34.91%/57.99% (R3K342) |
37.02%/51.93% (P66037) |
N/A |
FAD synthetase (A0A2D2N1C2) | 36.08%/54.26% (A0A829BS71) |
33.24%/52.91% (A0A0M4SS57) |
33.71%/52.81% (A0A3N3ZCW2) |
36.52%/54.78% (A0A2X1VAD0) |
35.90%/54.70% (A0A428B2K5) |
N/A means the sequence information is not available in the database.
When the number of pathogenic oral microorganisms increases, the expression of virulence factors and biofilm production is promoted through quorum sensing69-71). Recent studies have revealed the detailed mechanisms and functions of the genes involved in sensing oral pathogens. Biofilm formation induces antibiotic resistance in oral pathogenic microorganisms by inhibiting antibiotic penetration of antibiotics72,73). During biofilm formation, oral microorganisms are directly connected to each other through adhesion proteins and exchange various metabolites for signaling74-76).
Several Oral Pathogens have Quorum Sensing Systems
Oral pathogen | Quorum sensing molecules | Quorum sensing type | Reference |
---|---|---|---|
Autoinducer-2 (AI-2) | LuxS-encoded autoinducer (AI)-2 quorum sensing | 83∼85 | |
Autoinducer-2 (AI-2) | LuxS-encoded autoinducer (AI)-2 quorum sensing | 84, 85 | |
Autoinducer-2 (AI-2) | LuxS-encoded autoinducer (AI)-2 quorum sensing | 85, 86 | |
Autoinducer peptides (AIPs) | ComD/ComE two-component-type quorum sensing | 87 | |
Competence-stimulating peptide (CSP) | |||
Autoinducer-2 (AI-2) | LuxS-encoded autoinducer (AI)-2 quorum sensing | 88 |
Summary of Quorum Sensing Inhibitors Targeting Oral Pathogens
Quorum sensing inhibitor | Inhibition target | Mechanism of action | Reference |
---|---|---|---|
Coumarin | Inhibiting AI-2 activity | 53, 54 | |
Furanone compound | |||
D-Ribose | Inhibiting AI-2 activity and reducing biofilm formation | 86, 89 | |
D-Galactose | Preventing biofilm formation | 90 | |
D-Arabinose | Inhibiting AI-2 activity | 91 | |
Short-chain fattyacids (NaA, NaP, NaB, etc.) |
Suppressing |
92 | |
Bicyclic brominated furanones | Inhibiting AI-2 activity without cytotoxicity or inflammatory response | 93 | |
Baicalein | Inhibiting biofilm formation and destruction | 94 | |
Furanone C-30 | Inhibiting biofilm formation in |
95 |
Rapid developments in molecular biology, genome analysis, and metabolite analysis technologies have enabled the identification of novel oral disease mechanisms in oral pathogens. Various signaling molecules and interacting proteins related to biofilm formation by certain oral pathogens have been identified. Proteins involved in the production of signaling molecules and signal transduction during biofilm formation can serve as new drug targets against oral pathogens. If drugs are developed to target proteins unique to oral pathogens, it would be possible to selectively eliminate oral pathogens, while preserving beneficial oral commensal microorganisms. Establishing a rapid and accurate activity measurement method for each new drug candidate target protein is also necessary. In conclusion, it is important to study the various mechanisms of action of oral pathogens and identify new target proteins to develop novel antibiotics against oral pathogens. In this review, we investigated six successful cases of confirmed antibacterial activity against oral pathogens using marine natural products. Most studies on the antibacterial activity of natural marine products have been conducted on general rather than oral pathogens. Therefore, it is necessary to investigate the application of substances with known antibacterial activities against oral pathogens. Moreover, it is important to screen for novel antibiotics in marine organisms to address the antibiotic resistance issues associated with oral diseases.
None.
No potential conflict of interest relevant to this article was reported.
Not applicable.
Conceptualization: Youn-Soo Shim and Jun Hyuck Lee. Data acquisition: Sehyeok Im. Formal analysis: Sehyeok Im. Funding: Jun Hyuck Lee. Supervision: Youn-Soo Shim and Jun Hyuck Lee. Writing-original draft: Sehyeok Im. Writing-review & editing: Youn-Soo Shim and Jun Hyuck Lee.
This research was supported by the project titled “Development of potential antibiotic compounds using polar organism resources (20200610, KOPRI Grant PM24030)”, funded by the Ministry of Oceans and Fisheries, Korea.
Raw data is provided by the corresponding author upon reasonable request.