Antibacterial effect of alpha-mangostin from Garcinia mangostana L against oral streptococci and staphylococci biofilms: a systematic review

Introduction: Interactions among competing bacteria, which inhibit each other's growth to maintain the balance of microorganisms in the biofilm, can influence oral cavity homeostasis. Natural products contain compounds with the potential to combat various diseases, including caries. Alpha-mangostin from Garcinia mangostana L exhibits antibacterial properties against oral streptococci and staphylococci, acting through several mechanisms, including the disruption of peptidoglycan, which ultimately leads to cell brittleness and rupture. This study aims to assess the impact of antibacterial alpha-mangostin on oral streptococci and staphylococci biofilm. Methods: The research methodology employed secondary data collection through a systematic review study. We conducted searches across databases including PubMed, ScienceDirect, and Google Scholar to identify Indonesian and English references encompassing textbooks, research findings, reviews, and internet articles relevant to the topic published between 2014 and 2024. Following a thorough screening process, we selected articles deemed pertinent for inclusion in the review. Subsequently, these articles underwent evaluation for full-text accessibility, language compatibility, and availability of information from the respective journals, resulting in the selection of 20 articles. Result: Analysis was carried out on 20 articles. Ten articles described the effects of alpha-mangosteen's inhibit oral biofilm, 6 articles discussed the effects of alpha-mangosteen's antibacterial activity against Streptococcus mutans and Streptococcus sanguis, 3 article state mechanism alpha-mangostin inhibit membrane enzymes such as F(H+)-ATPase and the phosphoenolpyruvate-sucrose phosphotransferase system on Staphylococcus aureus. Additionally, one article describe inhibition mechanism of aldolase, glyceraldehyde-3-phosphate dehydrogenase, and lactic dehydrogenase on Staphylococcus epidermidis. Conclusion: Alpha-mangostin inhibits and disrupts biofilm defense mechanisms. It possesses antimicrobial properties effective against oral streptococci and staphylococci, including Streptococcus mutans, Streptococcus sanguis, Staphylococcus aureus and Staphylococcus epidermidis. These properties operate through various mechanisms, including enhancing the permeability of bacterial cell walls, ultimately leading to bacterial cell death.


INTRODUCTION
Biofilms are surface-bound microbial communities enveloped by self-synthesizing extracellular polymeric substances such as proteins, polysaccharides, and nucleic acids. 1 Virulent biofilms are responsible for various infectious illnesses, including oral disease in humans.Dental caries, a prevalent and costly biofilm-dependent disease globally, stems from virulent biofilms. 2Bacterial cells within biofilms shield themselves within an intricate architecture, eluding host defense mechanisms Padjadjaran Journal of Dentistry • Volume 36, Number 2, July 2024 and antimicrobial agents, resulting in chronic and resistant infections. 3For microorganisms involved in caries progression, virulence factors such as the production of an extracellular polysaccharide-rich biofilm matrix, environmental acidification, and maintenance of an acidic pH microenvironment near tooth enamel must be controlled when addressing tooth decay development. 2,3rcinia mangostana Linn.(mangosteen) contains the antibacterial xanthone alpha-mangostin.Extensive reports on alpha-mangostin have demonstrated its broad pharmaceutical significance, including anti-inflammatory, anti-tumor , cardioprotective, anti-diabetic, antibacterial, antifungal, antiparasitic, antioxidant, antiobesity, and antibacterial activities. 4Alpha-mangostin, as a member of the xanthone class, is 9H-xanthene substituted by methoxy, oxo, and hydroxy groups at positions 7, 9, 2, with hydroxyl groups at positions 1, 3, and 6. 5  5 In vitro, alpha-mangostin (a-MG) exhibits rapid bactericidal activity against several gram-positive pathogens.Alpha-mangostin (a-MG) shows rapid bactericidal activity against several gram-positive pathogens in vitro. 6It rapidly damages the cytoplasmic membrane of methicillin-resistant Staphylococcus aureus (MRSA), leading to the loss of cytoplasmic components. 7Notably, previous studies have shown that gram-positive pathogens did not develop resistance to the natural product alpha-mangostin using a multi-step resistance selection assay. 4Alpha-mangostin has antibacterial properties that can reduce the thickness of the oral streptococci biofilm and is an effective antimicrobial agent against the planktonic cells of oral staphylococci.Hence, it is crucial to investigate the effect antibacterial of alpha-mangostin on biofilm formation in oral streptococci and staphylococci, because previously there had been no research combining the effects of alpha-mangostin on these oral streptococci and staphylococci especially Streptococcus mutans, Streptococcus sanguis, Staphylococcus aureus and Staphylococcus epidermidis.This study aims to assess the impact of antibacterial alpha-mangostin on oral streptococci and staphylococci biofilm.

METHODS
This study comprises a systematic review.This study used the keyword oral biofilm, alpha-mangostin, oral streptococci, Streptococcus mutans, Streptococcus sanguis, staphylococci, Staphylococcus aureus, and Staphylococcus epidermidis.
Each keyword with a phrase related to oral streptococci and staphylococci was utilized to conduct a thorough literature search across PubMed, ScienceDirect, and Google Scholar databases.Selected literature includes original or review articles published between 2014 and 2024, written in either Indonesian or English.
Journals not either of these languages and those lacking full-text availability were excluded, as were those failing to specify the nature of the work and exposure to chemical compounds of alpha mangostin.Following a thorough screening process, we selected articles deemed pertinent for inclusion in the review and articles that are not relevant to the discussion are excluded.Subsequently, these articles underwent evaluation for full-text accessibility, language compatibility, and availability of information from the respective journals, resulting in the selection of 20 articles.Mendeley, a reference management software, was employed to organize references and gather journal data.
Following the application of exclusion criteria, 20 articles were selected (explained in Diagram 1 in the PRISMA Flowchart).

RESULTS
In this study, literature was obtained from three databases: PubMed (n= 722), ScienceDirect (n= 1,086), and Google Scholar (n= 3,960).Subsequently, a skim reading of the abstracts and main bodies was conducted (n=125), followed by a thorough reading of the main bodies (n=60).
Analysis was carried out on 20 articles in table 1.Ten articles described the effects of alpha-mangosteen's inhibit oral biofilm, 6 articles discussed the effects of alpha-mangosteen's antibacterial activity against Streptococcus mutans and Streptococcus sanguis, 3 article state mechanism alpha-mangostin inhibit membrane enzymes such as F(H+)-ATPase and the phosphoenolpyruvate -

DISCUSSION
Interactions among competing bacteria, which inhibit each other's growth to maintain microbial balance within the biofilm, can significantly impact oral cavity homeostasis.Competitor bacterial activities, such as mutacin produced by Streptococcus mutans, can directly impede the growth of Streptococcus sanguis bacteria, and vice versa. 8atural products, predominantly derived from plants, harbor a plethora of compounds with potential for combating various diseases, including caries.Among these, several plant-based natural products exhibit inhibitory effects on Streptococcus mutans growth, primarily composed of polyphenolic compounds, notably flavonoids, based on their chemical structures. 15However, their precise mechanism of action against Streptococcus mutans survival remains unclear, with potential mechanisms including specific interactions with the cell membrane, altering its permeability and leading to cell death, as well as altering gene expression involved in biofilm formation at the transcriptional level.Additionally , some compounds can hinder enzyme activity in acid production pathways. 8pha-mangostin, a xanthone extracted from the tropical plant Garcinia mangostana L. through ethanolic extraction, inhibits S. mutans UA159 acid production.Mechanistic indicates that alpha-mangostin acts as a multitarget inhibitor, inhibiting membrane enzymes such as F(H+)-ATPase and the phosphoenolpyruvate-sucrose phosphotransferase system, as well as aldolase, glyceraldehyde-3-phosphate dehydrogenase, and lactic dehydrogenase.It inhibits glycolysis in intact cells in suspensions and biofilm formation at concentrations of 12 and 120 M, respectively.Other inhibitory effects of alpha-mangostin include malolactic fermentation involved in alkali production from malate and NADH oxidase, the primary respiratory enzyme for gram-positive bacteria. 9,10lpha-mangostin's antimicrobial properties against Gram-positive oral streptococcus bacteria operate through various mechanisms, including disrupting peptidoglycan, leading to cell brittleness and rupture, damaging the mechanical stability of Streptococcus mutans and Streptococcus sanguis biofilms, and inhibiting glucosyltransferase enzyme activity. 10Moreover, alpha-mangostin reduces acid production from Streptococcus mutans, damages the cell membranes of other microorganisms in biofilms, binds directly to bacterial cell inner membranes, and increases bacterial cell permeability, ultimately resulting in bacterial cell death. 10e rapid bactericidal activity of alpha-mangostin (a-MG) on Staphylococcus aureus, Staphylococcus epidermidis and other Gram-positive bacteria is noteworthy, as is its resistance to resistance development. 11The bactericidal activity of alpha-mangostin on biofilms is significantly influenced by the age of the biofilm, and it may prove more effective when combined with other antimicrobial compounds.11 Streptococcus mutans bacteria also produce gtfs, which is essential for extracellular matrix protein (EPS) formation.Similar to Streptococcus sanguis, Streptococcus mutans produces gtfB, gtfC, and gtfD, facilitating glucan formation and aiding in attachment to saliva-coated hydroxyapatite (sHA). 2 Bacteria then colonize and secrete extracellular polymeric substances (EPS) during the lag phase, initiating bacterial colonization and upregulating gene expression under aerobic conditions. 12Rapid and extensive bacterial multiplication leads to colony formation during the rapid growth or exponential phase. 12he previous rapid growth phase encompassed both primary and secondary bacterial colonization.Aerobic bacteria such as streptococci and staphylococci Padjadjaran Journal of Dentistry • Volume 36, Number 2, July 2024 species initially colonize the biofilm, multiplying and subsequently reducing oxygen availability within it.This paves the way for secondary bacterial colonization by anaerobic species like Actinomyces, Fusobacterium nucleatum, Prevotella intermedia, and Capnocytophaga. 14The steady state phase, also termed the stationary and death phase, is characterized by slow or stagnant bacterial growth, heightened extracellular polymeric substance (EPS) production, and decreased oxygen saturation resulting from bacterial activity in the preceding phase.Prolonged persistence in this state can enhance biofilm protection. 15he initial step in biofilm formation entails the development of a distinct biofilm architecture, achieved through both cell-to-cell and cell-to-surface interactions.In light of this, the impact of alpha-mangostin on these interactions was assessed.Findings indicated that inhibiting biofilm formation necessitated the addition of alpha-mangostin during the initial biofilm formation stages. 1 Disruption of glucan synthesis affects bacterial metabolism, thereby compromising the stability and strength of bacterial attachment within the biofilm. 16Across the three stages of biofilm formation, alpha-mangostin demonstrates inhibitory effects and damages biofilm defense mechanisms. 17.Furthermore, alpha-mangosteen exhibits several anti-streptococci and staphylococci activities, including reducing acid production, which can harm the cell membranes of other microorganisms within the biofilm, directly binding to bacterial cell inner membranes, and enhancing the permeability of alphamangostin in bacterial cells, ultimately leading to bacterial cell death. 18n vitro studies investigating the efficacy of mangosteen peel against cariogenic bacteria have revealed its potential to inhibit oral streptococci and staphylococci. 19,2Additional research delves into the effectiveness of alphamangostin and its biological action in combating the formation of oral bacterial biofilms in vitro, highlighting its ability to reduce biological mass accumulation, insoluble extracellular material, and enzyme activity for glucan synthesis. 2iscrepancies observed in the antibiofilm activity of alpha-mangostin among the test strains in this study could be attributed to differences in biofilm structure.One hypothesis posits that extracellular matrix components in biofilms, such as polysaccharides for NCTC 6175 and MSSA 15981, and surface proteins like FnBPA for MRSA 252, may interact variably with alpha-mangostin. 11umerous studies indicate that alpha-mangostin binds to various unrelated proteins, including human serum albumin, transferrin, and the ATP-binding cassette drug transporter ABCG2 in cancer cells.Previous research has demonstrated alpha-mangostin's interaction with membrane-bound enzymes like F-ATPase and phosphotransferase systems in oral streptococci, along with the catalytic domain of glucosyltransferase C, a key enzyme responsible for biofilm formation by this organism. 20,21,11The study investigate the effect antibacterial of alpha-mangostin on biofilm formation in oral streptococci and staphylococci, because previously there had been no research combining the effects of alphamangostin on these oral streptococci and staphylococci especially Streptococcus mutans, Streptococcus sanguis, Staphylococcus aureus and Staphylococcus epidermidis.The limitation of this research were difficulty to obtain the full text of articles and limited number of studies that meet the inclusion criteria means that the results may affect the representativeness of the articles.In addition, the studies included in this review differed in methodological quality, which may influence the validity of the results.

CONCLUSION
Alpha-mangostin from Garcinia mangostin L inhibits and disrupts biofilm defense mechanisms of oral bacterial biofilm, including Streptococcus mutans, Streptococcus sanguis, Staphylococcus aureus and Staphylococcus epidermidis.
These mechanisms operate to damage the cell membrane of microorganisms, bind directly to the inner membrane of bacterial cells, increase the permeability of bacterial cell walls which ultimately causes bacterial cell death, and reduce