Dental caries is the most prevalent and costly oral infectious disease worldwide. Virulent biofilms firmly attached to tooth surfaces are prime biological factors associated with this disease. The formation of an exopolysaccharide-rich biofilm matrix, acidification of the milieu and persistent low pH at the tooth-biofilm interface are major controlling virulence factors that modulate dental caries pathogenesis. Each one offers a selective therapeutic target for prevention. Although fluoride, delivered in various modalities, remains the mainstay for the prevention of caries, additional approaches are required to enhance its effectiveness. Available antiplaque approaches are based on the use of broad-spectrum microbicidal agents, e.g. chlorhexidine. Natural products offer a rich source of structurally diverse substances with a wide range of biological activities, which could be useful for the development of alternative or adjunctive anticaries therapies. However, it is a challenging approach owing to complex chemistry and isolation procedures to derive active compounds from natural products. Furthermore, most of the studies have been focused on the general inhibitory effects on glucan synthesis as well as on bacterial metabolism and growth, often employing methods that do not address the pathophysiological aspects of the disease (e.g. bacteria in biofilms) and the length of exposure/retention in the mouth. Thus, the true value of natural products in caries prevention and/or their exact mechanisms of action remain largely unknown. Nevertheless, natural substances potentially active against virulent properties of cariogenic organisms have been identified. This review focuses on gaps in the current knowledge and presents a model for investigating the use of natural products in anticaries chemotherapy. Copyright © 2011 S. Karger AG, Basel.453243263Aires, C.P., Tabchoury, C.P.M., Del Bel Cury, A.A., Koo, H., Cury, J.A., Effect of sucrose concentration on dental biofilm formed in situ and on enamel demineralization (2006) Caries Research, 40 (1), pp. 28-32. , DOI 10.1159/000088902Allaker, R.P., Douglas, C.W., Novel anti-microbial therapies for dental plaque-related diseases (2009) Int J Antimicrob Agents, 33, pp. 8-13Almas, K., Al-Zeid, Z., The immediate antimicrobial effect of a toothbrush and miswak on cariogenic bacteria: A clinical study (2004) J Contemp Dent Pract, 5, pp. 105-114Axelsson, P., Current role of pharmaceuticals in prevention of caries and periodontal disease (1993) Int Dent J, 43, pp. 473-482Bae, K., Jun, E.J., Lee, S.M., Paik, D.I., Kim, J.B., Effect of water-soluble reduced chitosan on Streptococcus mutans, plaque regrowth and biofilm vitality (2006) Clinical Oral Investigations, 10 (2), pp. 102-107. , DOI 10.1007/s00784-006-0038-3Bakkali, F., Averbeck, S., Averbeck, D., Idaomar, M., Biological effects of essential oils - A review (2008) Food and Chemical Toxicology, 46 (2), pp. 446-475. , DOI 10.1016/j.fct.2007.09.106, PII S0278691507004541Bakri, I.M., Douglas, C.W.I., Inhibitory effect of garlic extract on oral bacteria (2005) Archives of Oral Biology, 50 (7), pp. 645-651. , DOI 10.1016/j.archoralbio.2004.12.002, PII S0003996905000038Banas, J.A., Vickerman, M.M., Glucan-binding proteins of the oral streptococci (2003) Crit Rev Oral Biol Med, 14, pp. 89-99Bankova, V., Chemical diversity of propolis and the problem of standardization (2005) Journal of Ethnopharmacology, 100 (1-2), pp. 114-117. , DOI 10.1016/j.jep.2005.05.004, PII S0378874105003223, Perspectives of EthnopharmacologyBeighton, D., The complex oral microflora of high-risk individuals and groups and its role in the caries process (2005) Community Dentistry and Oral Epidemiology, 33 (4), pp. 248-255. , DOI 10.1111/j.1600-0528.2005.00232.xBennick, A., Interaction of plant polyphenols with salivary proteins (2002) Critical Reviews in Oral Biology and Medicine, 13 (2), pp. 184-196Bowen, W.H., Controversy: Do we need to be concerned about dental caries in the coming millennium? (2002) Critical Reviews in Oral Biology and Medicine, 13 (2), pp. 126-131Bowen, W.H., Koo, H., Biology of Streptococcus mutans -derived glucosyltransferases: Role in extracellular matrix formation of cariogenic biofilms (2011) Caries Res, 45, pp. 69-86Bowen, W.H., Pearson, S.K., Young, D.A., The effect of desalivation on coronal and root surface caries in rats (1988) J Dent Res, 67, pp. 21-23Brecx, M., Strategies and agents in supragingival chemical plaque control (1997) Periodontology 2000, 15 (1), pp. 100-108Brighenti, F.L., Luppens, S.B., Delbem, A.C., Deng, D.M., Hoogenkamp, M.A., Gaetti-Jardim Jr., E., Dekker, H.L., Ten Cate, J.M., Effect of Psidium cattleianum leaf extract on Streptococcus mutans viability, protein expression and acid production (2008) Caries Res, 42, pp. 148-154Busscher, H.J., Engels, E., Dijkstra, R.J., Van Der Mei, H.C., Influence of a chitosan on oral bacterial adhesion and growth in vitro (2008) Eur J Oral Sci, 116, pp. 493-495Cai, S., Simionato, M.R., Mayer, M.P., Novo, N.F., Zelante, F., Effects of subinhibitory concentrations of chemical agents on hydrophobicity and in vitro adherence of Streptococcus mutans and Streptococcus sanguis (1994) Caries Res, 28, pp. 335-341Castro, M.L., Cury, J.A., Rosalen, P.L., Alencar, S.M., Ikegaki, M., Duarte, S., Koo, H., Própolis do sudeste e nordeste do Brasil: Influěncia da sazonalidade na atividade antibacteriana e composição fenólica (2007) Quim Nova, 30. , DOI: 10.1590/S0100-40422007000700003Castro, M.L., Do Nascimento, A.M., Ikegaki, M., Costa-Neto, C.M., Alencar, S.M., Rosalen, P.L., Identification of a bioactive compound isolated from Brazilian propolis type 6 (2009) Bioorg Med Chem, 17, pp. 5332-5335Castro, M.L., Vilela, W.R., Zauli, R.C., Ikegaki, M., Rehder, V.L., Foglio, M.A., De Alencar, S.M., Rosalen, P.L., Bioassay guided purification of the antimicrobial fraction of a Brazilian propolis from Bahia state (2009) BMC Complement Altern Med, 9, p. 25Cheng, L., Exterkate, R.A., Zhou, X., Li, J., Ten Cate, J.M., Effect of Galla chinensis on growth and metabolism of microcosm biofilms (2011) Caries Res, 45, pp. 87-92Chinou, I., Primary and secondary metabolites and their biological activity (2008) Thin Layer Chromatography in Phytochemistry, pp. 59-76. , in Waksmundzka- Hajnos M, Sherma J, Kowalska T (eds) New York, CRCChoi, B.K., Kim, K.Y., Yoo, Y.J., Oh, S.J., Choi, J.H., Kim, C.Y., In vitro antimicrobial activity of a chitooligosaccharide mixture against Actinobacillus actinomycetemcomitans and Streptococcus mutans (2001) Int J Antimicrob Agents, 18, pp. 553-557Clardy, J., Walsh, C., Lessons from natural molecules (2004) Nature, 432 (7019), pp. 829-837. , DOI 10.1038/nature03194(2007), http://www.nap.edu/catalog/11970.html, Committee on Toxicity Testing and Assessment of Environmental Agents, National Research Council: Toxicity testing in the 21st century: A vision and a strategyCowan, M.M., Plant products as antimicrobial agents (1999) Clinical Microbiology Reviews, 12 (4), pp. 564-582Cross, S.E., Kreth, J., Zhu, L., Sullivan, R., Shi, W., Qi, F., Gimzewski, J.K., Nanomechanical properties of glucans and associated cell-surface adhesion of Streptococcus mutans probed by atomic force microscopy under in situ conditions (2007) Microbiology, 153 (9), pp. 3124-3132. , DOI 10.1099/mic.0.2007/007625-0Darout, I.A., Albandar, J.M., Skaug, N., Ali, R.W., Salivary microbiota levels in relation to periodontal status, experience of caries and miswak use in Sudanese adults (2002) Journal of Clinical Periodontology, 29 (5), pp. 411-420. , DOI 10.1034/j.1600-051X.2002.290505.xDuarte, S., Gregoire, S., Singh, A.P., Vorsa, N., Schaich, K., Bowen, W.H., Koo, H., Inhibitory effects of cranberry polyphenols on formation and acidogenicity of Streptococcus mutans biofilms (2006) FEMS Microbiol Lett, 257, pp. 50-56Duarte, S., Rosalen, P.L., Hayacibara, M.F., Cury, J.A., Bowen, W.H., Marquis, R.E., Rehder, V.L.G., Koo, H., The influence of a novel propolis on mutans streptococci biofilms and caries development in rats (2006) Archives of Oral Biology, 51 (1), pp. 15-22. , DOI 10.1016/j.archoralbio.2005.06.002, PII S0003996905001573Dürig, A., Kouskoumvekaki, I., Vejborg, R.M., Klemm, P., Chemoinformatics-assisted development of new anti-biofilm compounds Appl Microbiol Biotechnol, 2010 (87), pp. 309-317Dye, B.A., Tan, S., Smith, V., Lewis, B.G., Barker, L.K., Thornton-Evans, G., Eke, P.I., Li, C.H., Trends in oral health status: United States, 1988-1994 and 1999-2004 (2007) Vital Health Stat 11, 248, pp. 1-92Dzink, J.L., Socransky, S.S., Comparative in vitro activity of sanguinarine against oral microbial isolates (1985) Antimicrobial Agents and Chemotherapy, 27 (4), pp. 663-665Eley, B.M., Antibacterial agents in the control of supragingival plaque: A review (1999) Br Dent J, 186, pp. 286-296Fontana, M., Dunipace, A.J., Gregory, R.L., Noblitt, T.W., Li, Y., Park, K.K., Stookey, G.K., An in vitro Microbial Model for Studying Secondary Caries Formation (1996) Caries Research, 30 (2), pp. 112-118Fujiwara, M., Hayashi, Y., Ohara, N., Inhibitory effect of water-soluble chitosan on growth of Streptococcus mutans (2004) New Microbiologica, 27 (1), pp. 83-86Furiga, A., Lonvaud-Funel, A., Dorignac, G., Badet, C., In vitro anti-bacterial and anti-adherence effects of natural polyphenolic compounds on oral bacteria (2008) J Appl Microbiol, 105, pp. 1470-1476Godowski, K.C., Antimicrobial action of sanguinarine (1989) Journal of Clinical Dentistry, 1 (4), pp. 96-101Greenberg, M., Dodds, M., Tian, M., Naturally occurring phenolic antibacterial compounds show effectiveness against oral bacteria by a quantitative structure-activity relationship study (2008) J Agric Food Chem, 56, pp. 11151-11156Gregoire, S., Singh, A.P., Vorsa, N., Koo, H., Influence of cranberry phenolics on glucan synthesis by glucosyltransferases and Streptococcus mutans acidogenicity (2007) Journal of Applied Microbiology, 103 (5), pp. 1960-1968. , DOI 10.1111/j.1365-2672.2007.03441.xGroppo, F.C., De Cássia Bergamaschi, C., Cogo, K., Franz-Montan, M., Motta, R.H., De Andrade, E.D., Use of phytotherapy in dentistry (2008) Phytother Res, 22, pp. 993-998Groppo, F.C., Ramacciato, J.C., Simoes, R.P., Flório, F.M., Sartoratto, A., Antimicrobial activity of garlic, tea tree oil, and chlorhexidine against oral microorganisms (2002) Int Dent J, 52, pp. 433-437Guggenheim, B., Giertsen, E., Schupbach, P., Shapiro, S., Validation of an in vitro biofilm model of supragingival plaque (2001) Journal of Dental Research, 80 (1), pp. 363-370Leslie Gunatilaka, A.A., Berger, J.M., Evans, R., Miller, J.S., Wisse, J.H., Neddermann, K.M., Bursuker, I., Kingston, D.G.I., Isolation, synthesis, and structure - Activity relationships of bioactive benzoquinones from Miconia lepidota from the suriname rainforest (2001) Journal of Natural Products, 64 (1), pp. 2-5. , DOI 10.1021/np000219rHamada, S., Kontani, M., Hosono, H., Ono, H., Tanaka, T., Ooshima, T., Mitsunaga, T., Abe, I., Peroxidase-catalyzed generation of catechin oligomers that inhibit glucosyltransferase from Streptococcus sobrinus (1996) FEMS Microbiology Letters, 143 (1), pp. 35-40. , DOI 10.1016/0378-1097(96)00273-XHamilton-Miller, J.M.T., Anti-cariogenic properties of tea (Camellia sinensis) (2001) Journal of Medical Microbiology, 50 (4), pp. 299-302Hammer, K.A., Dry, L., Johnson, M., Michalak, E.M., Carson, C.F., Riley, T.V., Susceptibility of oral bacteria to Melaleuca alternifolia (tea tree) oil in vitro (2003) Oral Microbiology and Immunology, 18 (6), pp. 389-392. , DOI 10.1046/j.0902-0055.2003.00105.xHattori, M., Kusumoto, I.T., Namba, T., Ishigami, T., Hara, Y., Effect of tea polyphenols on glucan synthesis by glucosyltransferase from Streptococcus mutans (1990) Chemical and Pharmaceutical Bulletin, 38 (3), pp. 717-720Hayacibara, M.F., Koo, H., Rosalen, P.L., Duarte, S., Franco, E.M., Bowen, W.H., Ikegaki, M., Cury, J.A., In vitro and in vivo effects of isolated fractions of Brazilian propolis on caries development (2005) Journal of Ethnopharmacology, 101 (1-3), pp. 110-115. , DOI 10.1016/j.jep.2005.04.001, PII S0378874105002461Hayashi, Y., Ohara, N., Ganno, T., Yamaguchi, K., Ishizaki, T., Nakamura, T., Sato, M., Chewing chitosan-containing gum effectively inhibits the growth of cariogenic bacteria (2007) Archives of Oral Biology, 52 (3), pp. 290-294. , DOI 10.1016/j.archoralbio.2006.10.004, PII S0003996906002652Hirasawa, M., Shouji, N., Neta, T., Fukushima, K., Takada, K., Three kinds of antibacterial substances from Lentinus edodes (Berk.) Sing. (Shiitake, an edible mushroom) (1999) International Journal of Antimicrobial Agents, 11 (2), pp. 151-157. , DOI 10.1016/S0924-8579(98)00084-3, PII S0924857998000843Hirasawa, M., Takada, K., Otake, S., Inhibition of acid production in dental plaque bacteria by green tea catechins (2006) Caries Research, 40 (3), pp. 265-270. , DOI 10.1159/000092236Hirschfeld, I., (1939) The Toothbrush: Its Use and Abuse. A Treatise on Preventive Dentistry and Periodontia as Related to Dental Hygiene, , New York, Dental Items of Interest PublishingHoover, J.N., To, T., Efficacy of chlorhexidine and sanguinarine mouthrinses on selected salivary microflora (1990) J Can Dent Assoc, 56, pp. 325-327Ikeno, K., Ikeno, T., Miyazawa, C., Effects of propolis on dental caries in rats (1991) Caries Res, 25, pp. 347-351Inoue, Y., Shiraishi, A., Hada, T., Hirose, K., Hamashima, H., Shimada, J., The antibacterial effects of terpene alcohols on Staphylococcus aureus and their mode of action (2004) FEMS Microbiology Letters, 237 (2), pp. 325-331. , DOI 10.1016/j.femsle.2004.06.049, PII S0378109704004811Islam, B., Khan, S.N., Haque, I., Alam, M., Mushfiq, M., Khan, A.U., Novel anti-adherence activity of mulberry leaves: Inhibition of Streptococcus mutans biofilm by 1-deoxynojirimycin isolated from Morus alba (2008) J Antimicrob Chemother, 62, pp. 751-757Islam, B., Khan, S.N., Naeem, A., Sharma, V., Khan, A.U., Novel effect of plant lectins on the inhibition of Streptococcus mutans biofilm formation on saliva-coated surface (2009) J Appl Microbiol, 106, pp. 1682-1689Jagtap, A.G., Karkera, S.G., Extract of Juglandaceae regia inhibits growth, in-vitro adherence, acid production and aggregation of Streptococcus mutans (2000) Journal of Pharmacy and Pharmacology, 52 (2), pp. 235-242Jeon, J.G., Klein, M.I., Xiao, J., Gregoire, S., Rosalen, P.L., Koo, H., Influences of naturally occurring agents in combination with fluoride on gene expression and structural organization of Streptococcus mutans in biofilms (2009) BMC Microbiol, 9, p. 228Jones, W.P., Kinghorn, A.D., Extraction of plant secondary metabolites (2006) Natural Products Isolation, pp. 324-351. , in Sarker SD, Latif Z, Gray AI (eds) ed 3. New Jersey, HumanaKaufman, P.B., Cseke, L.J., Warber, S., Duke, J.A., Brielmann, H.L., (1999) Natural Products from Plants, , Boca Raton CRCKlein, M.I., Xiao, J., Heydorn, A., Koo, H., An analytical tool-box for comprehensive biochemical, structural and transcriptome evaluation of oral biofilms mediated by mutans streptococci J Vis Exp, , DOI: 10.3791/2512Koehn, F.E., Carter, G.T., The evolving role of natural products in drug discovery (2005) Nature Reviews Drug Discovery, 4 (3), pp. 206-220. , DOI 10.1038/nrd1657Koo, H., Strategies to enhance the biological effects of fluoride on dental biofilms (2008) Adv Dent Res, 20, pp. 17-21Koo, H., Cury, J.A., Rosalen, P.L., Ambrosano, G.M., Ikegaki, M., Park, Y.K., Effect of a mouthrinse containing selected propolis on 3-day dental plaque accumulation and polysaccharide formation (2002) Caries Res, 36, pp. 445-448Koo, H., Pearson, S.K., Scott-Anne, K., Abranches, J., Cury, J.A., Rosalen, P.L., Park, Y.K., Bowen, W.H., Effects of apigenin and tt-farnesol on glucosyltransferase activity, biofilm viability and caries development in rats (2002) Oral Microbiology and Immunology, 17 (6), pp. 337-343. , DOI 10.1034/j.1399-302X.2002.170602.xKoo, H., Rosalen, P.L., Cury, J.A., Park, Y.K., Bowen, W.H., Effects of compounds found in propolis on Streptococcus mutans growth and on glucosyltransferase activity (2002) Antimicrobial Agents and Chemotherapy, 46 (5), pp. 1302-1309. , DOI 10.1128/AAC.46.5.1302-1309.2002Koo, H., Hayacibara, M.F., Schobel, B.D., Cury, J.A., Rosalen, P.L., Park, Y.K., Vacca-Smith, A.M., Bowen, W.H., Inhibition of Streptococcus mutans biofilm accumulation and polysaccharide production by apigenin and tt-farnesol (2003) Journal of Antimicrobial Chemotherapy, 52 (5), pp. 782-789. , DOI 10.1093/jac/dkg449Koo, H., Jeon, J.G., Naturally occurring molecules as alternative therapeutic agents against cariogenic biofilms (2009) Adv Dent Res, 21, pp. 63-68Koo, H., Rosalen, P.L., Cury, J.A., Park, Y.K., Ikegaki, M., Sattler, A., Effect of Apis mellifera propolis from two Brazilian regions on caries development in desalivated rats (1999) Caries Res, 33, pp. 393-400Koo, H., Schobel, B., Scott-Anne, K., Watson, G., Bowen, W.H., Cury, J.A., Rosalen, P.L., Park, Y.K., Apigenin and tt-farnesol with fluoride effects on S. mutans biofilms and dental caries (2005) Journal of Dental Research, 84 (11), pp. 1016-1020. , DOI 10.1177/154405910508401109Koo, H., Seils, J., Abranches, J., Burne, R.A., Bowen, W.H., Quivey Jr., R.G., Influence of apigenin on gtf gene expression in Streptococcus mutans UA159 (2006) Antimicrobial Agents and Chemotherapy, 50 (2), pp. 542-546. , DOI 10.1128/AAC.50.2.542-546.2006Koo, H., Vacca Smith, A.M., Bowen, W.H., Rosalen, P.L., Cury, J.A., Park, Y.K., Effects of Apis mellifera propolis on the activities of streptococcal glucosyltransferases in solution and adsorbed onto saliva-coated hydroxyapatite (2000) Caries Res, 34, pp. 418-426Koo, H., Duarte, S., Murata, R.M., Scott-Anne, K., Gregoire, S., Watson, G.E., Singh, A.P., Vorsa, N., Influence of cranberry proanthocyanidins on formation of biofilms by Streptococcus mutans on saliva-coated apatitic surface and on dental caries development in vivo (2010) Caries Res, 44, pp. 116-126Koo, H., Xiao, J., Klein, M.I., Jeon, J.G., Exopolysaccharides produced by Streptococcus mutans glucosyltransferases modulate the establishment of microcolonies within multispecies biofilms (2010) J Bacteriol, 192, pp. 3024-3032Kopec, L.K., Bowen, W.H., Adherence of microorganisms to rat salivary pellicles (1995) Caries Res, 29, pp. 507-512Larson, R.M., Merits and modifications of scoring rat dental caries by Keyes' method (1981) Microbiology Abstracts. Animal Models in Cariology, pp. 195-203. , in Tanzer JM (ed) Oxford, IRL, special supplLemos, J.A., Abranches, J., Koo, H., Marquis, R.E., Burne, R.A., Protocols to study the physiology of oral biofilms Methods Mol Biol, 2010 (666), pp. 87-102Lemos, J.A., Burne, R.A., A model of efficiency: Stress tolerance by Streptococcus mutans (2008) Microbiology, 154, pp. 3247-3255Li, X.-C., Cai, L., Wu, C.D., Antimicrobial compounds from Ceanothus americanus against oral pathogens (1997) Phytochemistry, 46 (1), pp. 97-102. , DOI 10.1016/S0031-9422(97)00222-7, PII S0031942297002227Linke, H.A.B., LeGeros, R.Z., Black tea extract and dental caries formation in hamsters (2003) International Journal of Food Sciences and Nutrition, 54 (1), pp. 89-95. , DOI 10.1080/096374803/000062029Loesche, W.J., Role of Streptococcus mutans in human dental decay (1986) Microbiological Reviews, 50 (4), pp. 353-380Loesche, W.J., Henry, C.A., Intracellular microbial polysaccharide production and dental caries in a Guatemalan Indian Village (1967) Arch Oral Biol, 12, pp. 189-194Marquis, R.E., Clock, S.A., Mota-Meira, M., Fluoride and organic weak acids as modulators of microbial physiology (2003) FEMS Microbiology Reviews, 26 (5), pp. 493-510. , DOI 10.1016/S0168-6445(02)00143-2, PII S0168644502001432Marsh, P.D., Antimicrobial strategies in the prevention of dental caries (1993) Caries Res, 27 (SUPPL. 1), pp. 72-76Marsh, P.D., Are dental diseases examples of ecological catastrophes? (2003) Microbiology, 149 (2), pp. 279-294. , DOI 10.1099/mic.0.26082-0Matsumoto, M., Hamada, S., Ooshima, T., Molecular analysis of the inhibitory effects of oolong tea polyphenols on glucan-binding domain of recombinant glucosyltransferases from Streptococcus mutans MT8148 (2003) FEMS Microbiology Letters, 228 (1), pp. 73-80. , DOI 10.1016/S0378-1097(03)00723-7Matsumoto, M., Minami, T., Sasaki, H., Sobue, S., Hamada, S., Ooshima, T., Inhibitory effects of oolong tea extract on caries-inducing properties of mutans streptococci (1999) Caries Res, 33, pp. 441-445Matsumoto, M., Tsuji, M., Okuda, J., Sasaki, H., Nakano, K., Osawa, K., Shimura, S., Ooshima, T., Inhibitory effects of cacao bean husk extract on plaque formation in vitro and in vivo (2004) European Journal of Oral Sciences, 112 (3), pp. 249-252. , DOI 10.1111/j.1600-0722.2004.00134.xMcCabe, R.M., Donkersloot, J.A., Adherence of Veillonella species mediated by extracellular glucosyltransferase from Streptococcus salivarius (1977) Infection and Immunity, 18 (3), pp. 726-734Menezes, S.M.S., Cordeiro, L.N., Viana, G.S.B., Punica granatum (pomegranate) extract is active against dental plaque (2006) Journal of Herbal Pharmacotherapy, 6 (2), pp. 79-92. , DOI 10.1300/J157v06n02-07Murata, R.M., Branco De Almeida, L.S., Yatsuda, R., Dos Santos, M.H., Nagem, T.J., Rosalen, P.L., Koo, H., Inhibitory effects of 7-epiclusianone on glucan synthesis, acidogenicity and biofilm formation by Streptococcus mutans (2008) FEMS Microbiology Letters, 282 (2), pp. 174-181. , DOI 10.1111/j.1574-6968.2008.01117.xNakahara, K., Kawabata, S., Ono, H., Ogura, K., Tanaka, T., Ooshima, T., Hamada, S., Inhibitory effect of oolong tea polyphenols on glucosyltransferases of mutans streptococci (1993) Applied and Environmental Microbiology, 59 (4), pp. 968-973National Institutes of Health: Diagnosis and management of dental caries throughout life (2001) NIH Consens Statement, 18, pp. 1-30Newman, D.J., Cragg, G.M., Natural products as sources of new drugs over the last 25 years (2007) Journal of Natural Products, 70 (3), pp. 461-477. , DOI 10.1021/np068054vOoshima, T., Minami, T., Aono, W., Izumitani, A., Sobue, S., Fujiwara, T., Kawabata, S., Hamada, S., Oolong tea polyphenols inhibit experimental dental caries in SPF rats infected with mutans streptococci (1993) Caries Res, 27, pp. 124-129Ooshima, T., Minami, T., Aono, W., Tamura, Y., Hamada, S., Reduction of dental plaque deposition in humans by oolong tea extract (1994) Caries Res, 28, pp. 146-149Ooshima, T., Minami, T., Matsumoto, M., Fujiwara, T., Sobue, S., Hamada, S., Comparison of the cariostatic effects between regimens to administer oolong tea polyphenols in SPF rats (1998) Caries Research, 32 (1), pp. 75-80Ooshima, T., Osaka, Y., Sasaki, H., Osawa, K., Yasuda, H., Matsumura, M., Sobue, S., Matsumoto, M., Caries inhibitory activity of cacao bean husk extract in in-vitro and animal experiments (2000) Archives of Oral Biology, 45 (8), pp. 639-645. , DOI 10.1016/S0003-9969(00)00042-X, PII S000399690000042XOsawa, K., Miyazaki, K., Shimura, S., Okuda, J., Matsumoto, M., Ooshima, T., Identification of cariostatic substances in the cacao bean husk: Their anti-glucosyltransferase and antibacterial activities (2001) J Dent Res, 80, pp. 2000-2004Otake, S., Makimura, M., Kuroki, T., Nishihara, Y., Hirasawa, M., Anticaries effects of polyphenolic compounds from Japanese green tea (1991) Caries Res, 25, pp. 438-443Paes Leme, A.F., Koo, H., Bellato, C.M., Bedi, G., Cury, J.A., The role of sucrose in cariogenic dental biofilm formation - New insight (2006) Journal of Dental Research, 85 (10), pp. 878-887Pai, M.R., Acharya, L.D., Udupa, N., Evaluation of antiplaque activity of Azadirachta indica leaf extract gel - A 6-week clinical study (2004) Journal of Ethnopharmacology, 90 (1), pp. 99-103. , DOI 10.1016/j.jep.2003.09.035Park, Y.K., Alencar, S.M., Aguiar, C.L., Botanical origin and chemical composition of Brazilian propolis (2002) Journal of Agricultural and Food Chemistry, 50 (9), pp. 2502-2506. , DOI 10.1021/jf011432bPark, Y.K., Koo, M.H., Abreu, J.A.S., Ikegaki, M., Cury, J.A., Rosalen, P.L., Antimicrobial activity of propolis on oral microorganisms (1998) Current Microbiology, 36 (1), pp. 24-28. , DOI 10.1007/s002849900274Quivey Jr., R.G., Kuhnert, W.L., Hahn, K., Adaptation of oral streptococci to low pH (2000) Advances in Microbial Physiology, 42, pp. 239-274Rasooli, I., Shayegh, S., Taghizadeh, M., Astaneh, S.D., Phytotherapeutic prevention of dental biofilm formation (2008) Phytother Res, 22, pp. 1162-1167Rölla, G., Ciardi, J.E., Schultz, A.S., Adsorption of glucosyltransferase to saliva coated hydroxyapatite: Possible mechanism for sucrose dependent bacterial colonization of teeth (1983) Scand J Dent Res, 91, pp. 112-117Rosen, S., Elvin-Lewis, M., Beck, F.M., Beck, E.X., Anticariogenic effects of tea in rats (1984) J Dent Res, 63, pp. 658-660Saeki, Y., Kato, T., Naito, Y., Takazoe, I., Okuda, K., Inhibitory effects of funoran on the adherence and colonization of mutans streptococci (1996) Caries Research, 30 (2), pp. 119-125Sakanaka, S., Kim, M., Taniguchi, M., Yamamoto, T., Antibacterial substances in Japanese green tea extract against Streptococcus mutans, a cariogenic bacterium (1989) Agricultural and Biological Chemistry, 53 (9), pp. 2307-2311Salatino, A., Teixeira, E.W., Negri, G., Message, D., Origin and chemical variation of Brazilian propolis (2005) Evidence-based Complementary and Alternative Medicine, 2 (1), pp. 33-38. , DOI 10.1093/ecam/neh060Sasaki, H., Matsumoto, M., Tanaka, T., Maeda, M., Nakai, M., Hamada, S., Ooshima, T., Antibacterial activity of polyphenol components in oolong tea extract against Streptococcus mutans (2004) Caries Research, 38 (1), pp. 2-8. , DOI 10.1159/000073913Sato, S., Yoshinuma, N., Ito, K., Tokumoto, T., Takiguchi, T., Suzuki, Y., Murai, S., The inhibitory effect of funoran and eucalyptus extractcontaining chewing gum on plaque formation (1998) J Oral Sci, 40, pp. 115-117Scheie, A.A.A., Modes of action of currently known chemical anti-plaque agents other than chlorhexidine (1989) Journal of Dental Research, 68 (SPEC. ISS. NOV.), pp. 1609-1616Schilling, K.M., Bowen, W.H., The activity of glucosyltransferase adsorbed onto saliva-coated hydroxyapatite (1988) J Dent Res, 67, pp. 2-8Schilling, K.M., Bowen, W.H., Glucans synthesized in situ in experimental salivary pellicle function as specific binding sites for Streptococcus mutans (1992) Infect Immun, 60, pp. 284-295Schmidt, B.M., Ribnicky, D.M., Lipsky, P.E., Raskin, I., Revisiting the ancient concept of botanical therapeutics (2007) Nature Chemical Biology, 3 (7), pp. 360-366. , DOI 10.1038/nchembio0707-360, PII NCHEMBIO0707360Sforcin, J.M., Fernandes Jr., A., Lopes, C.A., Bankova, V., Funari, S.R., Seasonal effect on Brazilian propolis antibacterial activity (2000) J Ethnopharmacol, 73, pp. 243-249Shapiro, S., Guggenheim, B., The action of thymol on oral bacteria (1995) Oral Microbiol Immunol, 10, pp. 241-246Shapiro, S., Meier, A., Guggenheim, B., The antimicrobial activity of essential oils and essential oil components towards oral bacteria (1994) Oral Microbiol Immunol, 9, pp. 202-208Shinada, K., Tagashira, M., Watanabe, H., Sopapornamorn, P., Kanayama, A., Kanda, T., Ikeda, M., Kawaguchi, Y., Hop bract polyphenols reduced three-day dental plaque regrowth (2007) J Dent Res, 86, pp. 848-851Shouji, N., Takada, K., Fukushima, K., Hirasawa, M., Anticaries effect of a component from shiitake (an edible mushroom) (2000) Caries Res, 34, pp. 94-98Silva, B.B., Rosalen, P.L., Cury, J.A., Ikegaki, M., Souza, V.C., Esteves, A., Alencar, S.M., Chemical composition and botanical origin of red propolis, a new type of Brazilian propolis (2008) Evid Based Complement Alternat Med, 5, pp. 313-316Singer, A.C., Crowley, D.E., Thompson, I.P., Secondary plant metabolites in phytoremediation and biotransformation (2003) Trends in Biotechnology, 21 (3), pp. 123-130. , DOI 10.1016/S0167-7799(02)00041-0Song, J.H., Yang, T.C., Chang, K.W., Han, S.K., Yi, H.K., Jeon, J.G., In vitro effects of a fraction separated from Polygonum cuspidatum root on the viability, in suspension and biofilms, and biofilm formation of mutans streptococci (2007) J Ethnopharmacol, 112, pp. 419-425Spatafora, G., Rohrer, K., Barnard, D., Michalek, S., A streptococcus mutans mutant that synthesizes elevated levels of intracellular polysaccharide is hypercariogenic in vivo (1995) Infect Immun, 63, pp. 2556-2563Steinberg, D., Feldman, M., Ofek, I., Weiss, E.I., Effect of a high-molecular-weight component of cranberry on constituents of dental biofilm (2004) Journal of Antimicrobial Chemotherapy, 54 (1), pp. 86-89. , DOI 10.1093/jac/dkh254Stookey, G.K., McDonald Jr., J.L., Further studies of the cariostatic properties of tin (II) and oat hulls in the rat (1974) J Dent Res, 53, pp. 1398-1403Tagashira, M., Uchiyama, K., Yoshimura, T., Shirota, M., Uemitsu, N., Inhibition by hop bract polyphenols of cellular adherence and water-insoluble glucan synthesis of mutans streptococci (1997) Bioscience, Biotechnology and Biochemistry, 61 (2), pp. 332-335Takarada, K., Kimizuka, R., Takahashi, N., Honma, K., Okuda, K., Kato, T., A comparison of the antibacterial efficacies of essential oils against oral pathogens (2004) Oral Microbiology and Immunology, 19 (1), pp. 61-64. , DOI 10.1046/j.0902-0055.2003.00111.xTamesada, M., Kawabata, S., Fujiwara, T., Hamada, S., Synergistic effects of streptococcal glucosyltransferases on adhesive biofilm formation (2004) Journal of Dental Research, 83 (11), pp. 874-879Tang, G., Yip, H.-K., Cutress, T.W., Samaranayake, L.P., Artificial mouth model systems and their contribution to caries research: A review (2003) Journal of Dentistry, 31 (3), pp. 161-171. , DOI 10.1016/S0300-5712(03)00009-5Tanzer, J.M., Freedman, M.L., Fitzgerald, R.J., Virulence of mutants defective in glucosyltransferase, dextran-mediated aggregation, or dextranase activity (1985) Molecular Basis of Oral Microbial Adhesion, pp. 204-211. , in Mergenhagen SE, Rosan B (eds) Washington, American Society for MicrobiologyTanzer, J.M., Freedman, M.L., Woodiel, F.N., Eifert, R.L., Rinehimer, L.A., Association of Streptococcus mutans virulence with synthesis of intracellular polysaccharide (1976) Proceedings in Microbiology. Aspects of Dental Caries, 3, pp. 596-616. , in Stiles HM, Loesche WJ, O'Brien TL (eds) London, Information RetrievalTarsi, R., Muzzarelli, R.A.A., Guzman, C.A., Pruzzo, C., Inhibition of Streptococcus mutans adsorption to hydroxyapatite by low-molecular-weight chitosans (1997) Journal of Dental Research, 76 (2), pp. 665-672Touyz, L.Z.G., Amsel, R., Anticariogenic effects of black tea (Camellia sinensis) in caries prone-rats (2001) Quintessence International, 32 (8), pp. 647-650Twetman, S., Antimicrobials in future caries control? A review with special reference to chlorhexidine treatment (2004) Caries Research, 38 (3), pp. 223-229. , DOI 10.1159/000077758Vacca-Smith, A.M., Bowen, W.H., Binding properties of streptococcal glucosyltransferases for hydroxyapatite, saliva coated hydroxyapatite, and bacterial surfaces (1998) Archives of Oral Biology, 43 (2), pp. 103-110. , DOI 10.1016/S0003-9969(97)00111-8, PII S0003996997001118Van Loveren, C., Sugar alcohols: What is the evidence for caries-preventive and caries-therapeutic effects? (2004) Caries Research, 38 (3), pp. 286-293. , DOI 10.1159/000077768Venkitaraman, A.R., Vacca-Smith, A.M., Kopec, L.K., Bowen, W.H., Characterization of glucosyltransferase B, GtfC, and GtfD in solution and on the surface of hydroxyapatite (1995) J Dent Res, 74, pp. 1695-1701Verpoorte, R., Choi, Y.H., Kim, H.K., Ethnopharmacology and systems biology: A perfect holistic match (2005) Journal of Ethnopharmacology, 100 (1-2), pp. 53-56. , DOI 10.1016/j.jep.2005.05.033, PII S037887410500348X, Perspectives of EthnopharmacologyVogel, J.J., Thompson, D.J., Phillips, P.H., Studies on the anticariogenic activity of oat hulls (1962) J Dent Res, 41, pp. 707-712Wen, D., Liu, Y., Li, W., Liu, H., Separation methods for antibacterial and antirheumatism agents in plant medicines (2004) Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, 812 (1-2 SPEC. ISS.), pp. 101-117. , DOI 10.1016/j.jchromb.2004.06.049, PII S1570023204005501Wolinsky, L.E., Mania, S., Nachnani, S., Ling, S., The inhibiting effect of aqueous Azadirachta indica (Neem) extract upon bacterial properties influencing in vitro plaque formation (1996) Journal of Dental Research, 75 (2), pp. 816-822Wolinsky, L.E., Sote, E.O., Isolation of natural plaque-inhibiting substances from 'Nigerian chewing sticks (1984) Caries Res, 18, pp. 216-225Wong, L., Sissions, C.H., A comparison of human dental plaque microcosm biofilms grown in an undefined medium and a chemically defined artificial saliva (2001) Archives of Oral Biology, 46 (6), pp. 477-486. , DOI 10.1016/S0003-9969(01)00016-4, PII S0003996901000164Wu, K.M., Ghantous, H., Birnkrant, D.B., Current regulatory toxicology perspectives on the development of herbal medicines to prescription drug products in the United States (2008) Food Chem Toxicol, 6, pp. 2606-2610Wunder, D., Bowen, W.H., Action of agents on glucosyltransferases from Streptococcus mutans in solution and adsorbed to experimental pellicle (1999) Archives of Oral Biology, 44 (3), pp. 203-214. , DOI 10.1016/S0003-9969(98)00129-0, PII S0003996998001290Wu-Yuan, C.D., Chen, C.Y., Wu, R.T., Gallotannins inhibit growth, water-insoluble glucan synthesis, and aggregation of mutans streptococci (1988) J Dent Res, 67, pp. 51-55Xiao, J., Koo, H., Structural organization and dynamics of exopolysaccharide matrix and microcolonies formation by Streptococcus mutans in biofilms (2010) J Appl Microbiol, 108, pp. 2103-2113Xie, Q., Li, J., Zhou, X., Anticaries effect of compounds extracted from Galla chinensis in a multispecies biofilm model (2008) Oral Microbiol Immunol, 23, pp. 459-465Yamanaka, A., Kimizuka, R., Kato, T., Okuda, K., Inhibitory effects of cranberry juice on attachment of oral streptococci and biofilm formation (2004) Oral Microbiology and Immunology, 19 (3), pp. 150-154. , DOI 10.1111/j.0902-0055.2004.00130.xYamashita, Y., Bowen, W.H., Burne, R.A., Kuramitsu, H.K., Role of the Streptococcus-mutans gtf genes in caries induction in the specific-pathogen-free rat model (1993)