Open access peer-reviewed chapter

Bacterial Cell-Free Probiotics Using Effective Substances Produced by Probiotic Bacteria, for Application in the Oral Cavity

Written By

Tomoko Ohshima, Tomomi Kawai and Nobuko Maeda

Submitted: July 20th, 2019 Reviewed: August 3rd, 2019 Published: September 12th, 2019

DOI: 10.5772/intechopen.89008

Chapter metrics overview

776 Chapter Downloads

View Full Metrics

Abstract

To avoid side effects of conventional antibiotics and disinfectants used for prevention of oral diseases such as dental caries, periodontitis, and oral candidiasis, application of probiotics has attracted attention recently. However, difficulties arise when applying those probiotics in the oral cavity, because exogenous probiotic bacteria do not colonize easily in the established oral microbiota. Even, if we are able to overcome the restriction of colonization by probiotic bacteria in the oral cavity, it comes with the risk of dental caries due to the potential acidic environment generated by probiotic bacteria. To solve these problems, “biogenics,” bacterial cell-free probiotics using only the effective substances metabolically produced by probiotic bacteria, is recommended for application in the oral cavity. The concept and frontline of biogenic research will be introduced and discussed.

Keywords

  • biogenics
  • probiotics
  • oral diseases
  • dental caries
  • periodontitis
  • candidiasis

1. Introduction

More than 700 bacterial species live in the oral cavity [1, 2]. These bacteria form their own indigenous flora in their habitats, such as teeth, gingival sulcus, and tongue dorsum, making the oral environment considerably complicated. Oral indigenous bacteria coexist with humans and are vital for preventing colonization by foreign pathogenic microorganisms in the oral cavity. Such oral indigenous bacteria proliferate with time, and together with the extracellular polymeric substance (EPS) that they produce, form a biofilm visible even to the naked eye known as dental plaque [3, 4, 5].

It has recently been clarified that the formation of biofilms is controlled by quorum-sensing (QS) signals in a communication system between microorganisms that sense each other’s abundance [6, 7, 8]. It has further been shown that microorganisms constituting a biofilm activate the expression of pathogenic factors when QS signaling molecules, so-called “autoinducers (AI),” act as transcription factors [8].

Advertisement

2. The potential pathogenicity of dental plaque as oral biofilm

Oral plaque contains also dental caries and periodontal disease causing organisms [9, 10, 11, 12], and when these exert their potential pathogenicity, they are considered to accelerate biofilm formation even more. Generally it can be said that with increasing thickness of the biofilm, the bacterial metabolites build up at the bottom of the biofilm, and the caries and periodontitis occurrence proliferate.

Caries and periodontal diseases are called the two major dental diseases, and both of them occur as oral infectious diseases which are caused by specific bacteria known as cariogenic bacteria (such as Streptococcus mutans) and periodontal pathogens (such as Porphyromonas gingivalis) growing in plaque. This status is interpreted as dysbiosis of the oral flora. In addition, a small number of fungal genus Candida is also present in the indigenous oral resident microflora, and some factors also cause its growth in the plaque, resulting in dysbiosis, which causes a major oral mucosal disease, oral candidiasis. However, there is currently no technique to selectively eliminate only those causative microorganisms from the flora.

Advertisement

3. Oral application of probiotics and problems

The method of preventing caries and periodontal disease is basically the mechanical removal of the entire plaque by brushing, etc. However in the case of onset of the disease, antimicrobial drugs are administered for the treatment of the acute phase of periodontal disease, and antifungal administration is the first choice for treatment of oral candidiasis. However, the use of antimicrobial agents has shown problems regarding adverse effects such as drug-resistant bacteria and allergies, indicating the limitation of chemotherapy [13]. Therefore, attention has recently focused on probiotic bacteria such as bifidobacteria and lactobacilli recognizing the usefulness for improving dysbiosis [14]. Although probiotics were originally intended to improve dysbiosis of the intestinal flora [15], their usefulness is also assumed in the dental field. Attempts have been made for direct use in the oral cavity to prevent diseases such as caries and periodontal disease, and several results have been reported [16, 17, 18]. Ishikawa et al. reported that 4 weeks of oral administration of Lactobacillus salivarius TI 2711 (LS1) significantly reduced the major periodontal pathogens of P. gingivalis, Prevotella intermedia, and Prevotella nigrescens [19].

However, in these reports, there are few basic facts on the effects of probiotics on the oral flora and the antibacterial substances produced by them, so progress and establishment of practical applications based on the underlying mechanism has not been accomplished. In addition, genera Lactobacillus and Bifidobacterium, which are representative probiotic bacteria, exist though in minority in the oral microbiota, but because they metabolize sugar and produce large amounts of organic acid, the general understanding is that they work cooperatively with cariogenic bacteria or induce hypersensitivity.

As another fundamental issue, previous studies have highlighted the limitation of colonization and fixation of nonnatural probiotic bacteria in the intestinal tract [20, 21]. This phenomenon of transiency, but not permanency in colonization, is also relevant for probiotic applications in the oral cavity [16, 22, 23]. Even if we are able to address the restriction of colonization of probiotic bacteria in the oral cavity, it comes with the risk of dental caries due to the potential acidic environment generated by probiotic bacteria.

Advertisement

4. The concept of biogenics

To overcome the above problems, “biogenics” as a new idea has been introduced. Biogenics is a kind of functional food, using only the ingredients, which have a positive effect on the host with regard to immunostimulating or immunosuppressing mutagenesis, tumorigenesis, peroxidation, hypercholesterolemia, or intestinal putrefaction [24]. Achieving a probiotic effect by the intake of nonviable probiotic bacteria has been proposed in previous reports. For example, the life span of mice increased, when they were fed with pasteurized fermented milk [25, 26]. A significant reduction of the Ehrlich ascites tumor growth in mice was also reported [26]. In addition, it was shown that heat-inactivated Enterococcus faecalis [27] or L. gasseri [28] showed a beneficial regulatory effect in the gut. Moreover, Nakamura et al. [29] found an angiotensin-I-converting enzyme (ACE) inhibitor in a Japanese sterilized milk beverage fermented by L. helveticus and Saccharomyces cerevisiae. The active substance in this fermented beverage was identified as lactotripeptide metabolically generated in the fermentation pathway. Follow-up studies were able to determine the bioactive metabolites of probiotic bacteria in addition to the antimicrobial substances, such as bacteriocin [30, 31], and other beneficial active substances, such as conjugated linoleic acid (CLA) [30, 31, 32], proteins or peptides [33, 34], and polyphenols [35, 36]. Taking all these observations into account, biogenics, which makes use of the bioactive metabolites as foods or medicine, was recently advocated as a new concept [24, 37]. The biogenic effect is independent of the colonization and viability of probiotic bacteria. Hence, biogenics is the direct delivery of an isolated and purified active ingredient of probiotics to the local environment. This strategy may also be useful for oral disease prevention. It may be possible to purify the effective ingredients against oral pathogenic activity of probiotic bacteria for use in the biogenics process. However, this idea requires further study prior to clinical use.

Advertisement

5. Antibacterial substances produced by lactic acid bacteria

Research of probiotics for intestinal health has revealed several antibacterial substances produced by lactic acid bacteria in addition to organic acids such as lactic and acetic acids [38]. These are (1) hydrogen peroxide [39], (2) bacteriocins [40], and (3) low-molecular-weight antimicrobial substances.

5.1 Hydrogen peroxide (H2O2)

Hydrogen peroxide is produced by most lactobacilli in the presence of oxygen. lactobacilli possess oxidases that reduce oxygen to hydrogen peroxide, oxidizing substrates such as pyruvate or NADH [41]. Since they do not produce catalases, H2O2 does not suffer auto-degradation. H2O2 has a broad-spectrum planktonic bacteria, but the effect decreases dramatically on biofilm. It appears that Lactobacilli do not produce effective concentrations of H2O2 against fungi [42], unlike other bacteria [39].

5.2 Bacteriocins

Lactic acid bacteria produce bacteriocins, proteinaceous antimicrobial substances with molecular weights of several thousand daltons or more. Bacteriocins can be divided into five classes according to their primary structure, molecular composition, and physical and functional properties [43, 44]. However, bacteriocins produced by lactic acid bacteria against S. mutans and P. gingivalis are not yet known. Bacteriocin L23 produced by Lactobacillus fermentum L23 [44], plantaricin produced by L. plantarum [45], and pentocin TV35b produced by L. pentosus [46] appear to be effective against the yeast form of Candida. Bacteriocins effective for the hyphal forms of Candida have not yet been identified [47, 48].

5.3 Low-molecular-weight antimicrobial substances

Reuterin, an antibacterial substance (also known as 3-hydroxypropionaldehyde; molecular weight, 74 Da; composition formula, C3H6O2), is a product of glycerol fermentation, which has been seen in several probiotic bacteria. These probiotic bacteria include not only L. reuteri [49] but also L. brevis, L. buchneri [50], and L. collinoides [51]. Under anaerobic conditions L. coryniformis [52] also produces a low-molecular-weight antimicrobial substance that does not contain amino acids [53]. Reuterin was found to exert its antibacterial effects by causing oxidative stress within the bacterial cell [54]. In addition to reuterin, the low-molecular-weight substances of lactobacilli, reutericyclin [55] and diacetyl [56] also showed effectiveness against the yeast forms of Candida [57].

As the smallest peptides, diketopiperazines (DKPs, cyclic dipeptides) are known to possess several physiological activities, including an antimicrobial effect.

diketopiperazines are a group of cyclic organic compounds where two amino acids are connected by a peptide bond, forming a lactam, and it is the first peptide whose three-dimensional structure has been completely solved by Robert Corey in the 1930s [58]. Corey determined the structure of the cyclic anhydride of the dipeptide glycylglycine. Diketopiperazines are also biosynthesized from amino acids in diverse organisms including mammals and are considered to be secondary metabolites [59]. Although some protease enzymes, such as dipeptidyl peptidase, produce a dipeptide by cleavage from the protein terminus, it is known that the resulting dipeptide cyclizes spontaneously to form a diketopiperazine. In addition, diketopiperazines are attractive scaffolds for drug design due to their structural properties such as a rigid structure, optical activity, and various side-chain structures [59]. Both natural diketopiperazines and synthetic diketopiperazines have been reported to possess various physiological activities including antitumor activity [60], antiviral activity [61], antibacterial activity [62], and antimicrobial activity [63]. However, there are only few reports on DKP produced by probiotic bacteria (Table 1). In addition, the antimicrobial mechanism is also poorly understood.

Cyclic dipeptideOriginBiological functionReferences
Cyclo(Leu-Pro)Lactobacillus casei AST18Antifungal activity[64]
Cyclo(Phe-Pro)L. plantarum MiLAB393Antifungal activity[65]
Cyclo(Phe-4-OH-Pro)
Cyclo(Gly-Leu)L. plantarum VTT E-78076Antimicrobial activity[66]
Cyclo(Phe-Pro)L. reuteri RC-14Antimicrobial activity[67]
Cyclo(Tyr-Pro)
Cyclo(Pro-Pro)L. amylovorus DSM 19280Antifungal activity[68]
Cyclo(Leu-Pro)
Cyclo(Met-Pro)
Cyclo(His-Pro)
Cyclo(Leu-Leu)L. plantarum AF1Antifungal activity[69]
Cyclo(4-OH-Pro-Leu)L. fermentum ALAL020Antimicrobial activity[70]

Table 1.

Diketopiperazines (cyclic dipeptide) produced by probiotic bacteria.

Advertisement

6. Anti-inflammatory substances produced by lactic acid bacteria

Periodontitis and candidiasis are both inflammatory diseases; therefore, inflammation symptoms are desired to be cured by biogenics, but there are few candidates for that.

CLA is a general term for regioisomers and structural isomers of linoleic acid having a conjugated diene structure.

Diene structure means there are two double bonds with a single bond in between. Rumenic acid, for example, is one of the 28 isomers of CLAs and exists in the fat and dairy products of ruminants [71]. It is a trans fat; however, CLAs can also appear as cis-fats. CLAs are known to reduce the production level of IgE and a chemical mediator leukotriene in a rat inflammatory model [72]. However, the opposite effect of increasing serum C-reactive protein value and reducing serum adiponectin level in human by CLA supplementation was observed recently [73].

Advertisement

7. Understanding the property of biofilm

Most bacteria and fungi have the potential to grow in a biofilm, in an environment with liquid flow and solid surfaces. Biofilm formation, which has been experimentally observed in single bacteria, is now known not only to cross species but also to cross the kingdom of microbes. In human bodies, such situations particularly exist in the resident microbiota. Microorganisms including oral pathogens have the potential to express pathogenic properties in biofilms, contrary to the planktonic type. In other words, the so-called biofilm phenotypes upregulate the production of EPS that block the stimuli or stress from outside the biofilm, such as antibiotics and disinfectants. The EPS also provides sticky intercellular binding material and extracellular energy storage compounds [74, 75] to promote interaction among contacting microbial cells [76], resulting in complex and dynamic interplay.

Advertisement

8. Disruption of the quorum-sensing signals

Recently, a QS inhibitor (QSI) and QS signal quencher (QQ) molecule attracted attention in regard to understanding biofilm infections. Biofilm formation is triggered and controlled by a cell-to-cell communication process in harmony with the bacterial population density known as quorum-sensing system, which is based on small molecules termed autoinducers [77]. Some reports revealed that bacteriocins produced by probiotic lactobacilli such as L. acidophilus, L. plantarum, and L. reuteri functioned as QSI or QQ molecules [78]. It may be possible to purify the effective ingredients of probiotic bacteria against oral pathogenic activity in biofilms for use in the biogenics process. Recently, some instance of QC disruption by cyclic dipeptides has been reported. L. reuteri, a human vaginal isolate, was capable of producing the cyclic dipeptides cyclo(L-Phe-L-Pro) and cyclo(L-Tyr-L-Pro), inhibiting the staphylococcal quorum-sensing system driven by the AI named agr, to suppress the expression of toxic shock syndrome toxin-1 in S. aureus [79]. The report is useful for a better understanding of interspecies cell-to-cell communication between Lactobacillus and Staphylococcus and provides a hint to attenuate virulence factor production by bacterial pathogens. However, this idea requires further study before clinical application.

Advertisement

9. Conclusion

Biogenics is based on the concept of using the active ingredients which were revealed by the mechanism of oral probiotics. Biogenics is expected to be a prevention method for oral diseases that can be implemented without the problems associated with the use of probiotic bacteria, namely the involvement of acids harmful to teeth. The emergence of resistant bacteria against naturally occurring substances of biogenic candidates is not yet known. Furthermore, it is possible to combine substances which contribute to the health of the oral cavity, with those contributing to systemic health, such as control substances for blood sugar level, blood pressure, neutral fat, antioxidants, anti-stress, immune enhancement, anti-inflammation, antianxiety, and antidepressants. Therefore, the progress of practical application is expected. However, the elucidation of the mechanism of action is still in the beginning, and further study is needed.

Advertisement

Acknowledgments

A part of this study was supported by JSPS KAKENHI Grant Number JP18K17057 and MEXT-Supported Program for the Strategic Research Foundation at Private Universities, 2015–2019.

Conflict of interest

There are no conflicts of interest.

References

  1. 1. Paster BJ, Olsen I, Aas JA, Dewhirst FE. The breadth of bacterial diversity in the human periodontal pocket and other oral sites. Periodontology 2000. 2006;42(1):80-87
  2. 2. Marsh PD, Devine DA. How is the development of dental biofilms influenced by the host? Journal of Clinical Periodontology. 2011;38:28-35
  3. 3. Sutherland IW. Biofilm exopolysaccharides: A strong and sticky framework. Microbiology. 2001;147:3-9
  4. 4. Bales PM. Purification and characterization of biofilm-associated EPS exopolysaccharides from ESKAPE organisms and other pathogens. PLoS One. 2013;8(6):e67950
  5. 5. Koo H. The exopolysaccharide matrix: A virulence determinant of cariogenic biofilm. Journal of Dental Research. 2013;92(12):1065-1073
  6. 6. Melissa B. Quorum sensing in bacteria. Annual Review of Microbiology. 2001;55:165-199
  7. 7. de Kievit TR et al. Quorum sensing in Pseudomonas aeruginosa biofilms. Environmental Microbiology. 2001;11(2):279-288
  8. 8. Li YH, Tian X. Quorum sensing and bacterial social interactions in biofilms. Sensors (Basel). 2012;12(3):2519-2538
  9. 9. Marsh PD, Bradshaw DJ. Dental plaque as a biofilm. Journal of Industrial Microbiology. 1995;15(3):169-175
  10. 10. Stralfors A. Studies of the microbiology of caries; the buffer capacity of the dental plaques. Journal of Dental Research. 1948;27(5):587-592
  11. 11. Poole DF, Newman HN. Dental plaque and oral health. Nature. 1971;234(5328):329-331
  12. 12. Axelsson P, Lindhe J. The effect of a plaque control program on gingivitis and dental caries in schoolchildren. Journal of Dental Research. 1971;56(C):142-148
  13. 13. Watanabe T. Infectious drug resistance in enteric bacteria. The New England Journal of Medicine. 1966;275:888-894
  14. 14. Gupta G. Probiotics and periodontal health. Journal of Medicine and Life. 2011;4:387-394
  15. 15. Fuller R. Probiotics in man and animals. The Journal of Applied Bacteriology. 1989;66:365-378
  16. 16. Krasse P, Carlsson B, Dahl C, Paulsson A, Nilsson A, Sinkiewicz G. Decreased gum bleeding and reduced gingivitis by the probiotic Lactobacillus reuteri. Swedish Dental Journal. 2006;30:55-60
  17. 17. Vivekananda MR, Vandana KL, Bhat KG. Effect of the probiotic Lactobacilli reuteri (Prodentis) in the management of periodontal disease: A preliminary randomized clinical trial. Journal of Oral Microbiology. 2010;2:2. DOI: 10.3402/jom.v2i0.5344
  18. 18. Riccia DN, Bizzini F, Perilli MG, Polimeni A, Trinchieri V, Amicosante G, et al. Anti-inflammatory effects of Lactobacillus brevis (CD2) on periodontal disease. Oral Diseases. 2007;13:376-385
  19. 19. Ishikawa H, Aiba Y, Nakanishi M, Oh-Hashi Y, Koga Y. Suppression of periodontal pathogenic bacteria by the administration of Lactobacillus salivarius TI2711. Journal of the Japanese Society of Periodontology. 2003;45:105-112
  20. 20. Haenel H. Aspekte der mikroökologischen beziehungen des makroorganismus. Mikroorganismen im menschlichen und tierischen darm und in anderen organen. Zentralblatt für Bakteriologie. 1960;176:305-426
  21. 21. Mitsuoka T, Kaneuchi C. Ecology of the bifidobacteria. The American Journal of Clinical Nutrition. 1977;30:1799-1810
  22. 22. Meurman JH, Antila H, Salminen S. Recovery of Lactobacillus strain GG (ATCC 53103) from saliva of healthy volunteers after consumption of yoghurt prepared with the bacterium. Microbial Ecology in Health and Disease. 1994;7(6):295-298
  23. 23. Caglar E, Topcuoglu N, Cildir SK, Sandalli N, Kulekci G. Oral colonization by Lactobacillus reuteri ATCC 55730 after exposure to probiotics. International Journal of Paediatric Dentistry. 2009;19(5):377-381
  24. 24. Mitsuoka T. Significance of dietary modulation of intestinal flora and intestinal environment. Bioscience and Microflora. 2000;19(1):15-25
  25. 25. Arai K, Murota I, Hayakawa K, Kataoka M, Mitsuoka T. Effects of administration of pasteurized fermented milk to mice on the life-span and intestinal flora. Journal of Japan Society of Nutrition and Food Sciences. 1980;33:219-223 [Japanese]
  26. 26. Takano T, Arai K, Murota I, Hayakawa K, Mizutani T, Mitsuoka T. Effects of feeding sour milk on longevity and tumorigenesis in mice and rats. Bifidobacteria and Microflora. 1985;4(1):31-37
  27. 27. Terada A, Bukawa W, Kan T, Mitsuoka T. Effects of the consumption of heat-killed enterococcus faecalis EC-12 preparation on microbiota and metabolic activity of the faeces in healthy adults. Microbial Ecology in Health and Diseases. 2004;16:188-194
  28. 28. Sawada D, Sugawara T, Ishida Y, Aihara K, Aoki Y, Takehara I, et al. Effect of continuous ingestion of a beverage prepared with Lactobacillus gasseri CP2305 inactivated by heat treatment on the regulation of intestinal function. Food Research International. 2016;79:33-39
  29. 29. Nakamura Y, Yamamoto N, Sakai K, Okubo A, Yamazaki S, Takano T. Purification and characterization of angiotensin I-converting enzyme inhibitors from sour milk. Journal of Dairy Science. 1995;78:777-783
  30. 30. Ross RP, Mills S, Hill C, Fitzgerald GF, Stanton C. Specific metabolite production by gut microbiota as a basis for probiotic function. International Dairy Journal. 2010;20:269-276
  31. 31. O'Shea EF, Cotter PD, Stanton C, Ross RP, Hill C. Production of bioactive substances by intestinal bacteria as a basis for explaining probiotic mechanisms: Bacteriocins and conjugated linoleic acid. International Journal of Food Microbiology. 2012;152:189-205
  32. 32. Hayes M, Coakley M, O'sullivan L, Stanton C. Cheese as a delivery vehicle for probiotics and biogenic substances. Australian Journal of Dairy Technology. 2006;61:132
  33. 33. Möller NP, Scholz-Ahrens KE, Roos N, Schrezenmeir J. Bioactive peptides and proteins from foods: Indication for health effects. European Journal of Nutrition. 2008;47:171-182
  34. 34. Bogsan CS, Florence ACR, Perina N, Hirota C, Soares FASM, Silva RC, et al. Survival of Bifidobacterium lactis HN019 and release of biogenic compounds in unfermented and fermented milk is affected by chilled storage at 4°C. Journal of Probiotics and Health. 2013;4:114. DOI: 10.4172/2329-8901.1000114
  35. 35. Monagas M, Urpi-Sarda M, Sánchez-Patán F, Llorach R, Garrido I, Gómez-Cordovés C, et al. Insights into the metabolism and microbial biotransformation of dietary flavan-3-ols and the bioactivity of their metabolites. Food & Function. 2010;1:233-253
  36. 36. Dharmaraj S. Marine Streptomyces as a novel source of bioactive substances. World Journal of Microbiology and Biotechnology. 2010;26:2123-2139. DOI: 10.1139/cjm-2013-0785
  37. 37. Mitsuoka T. Development of functional foods. Bioscience of Microbiota, Food and Health. 2014;33(3):117-128
  38. 38. Taniguchi M, Nakazawa H, Takeda O, Kaneko T, Hoshino K, Tanaka T. Production of a mixture of antimicrobial organic acids from lactose by co-culture of Bifidobacterium longum and Propionibacterium freudenreichii. Bioscience, Biotechnology, and Biochemistry. 1998;62:1522-1527
  39. 39. Piard JC, Desmazeaud M. Inhibiting factors produced by lactic acid bacteria. 1. Oxygen metabolites and catabolism end-products. Le Lait. 1991;71(5):525-541
  40. 40. Klaenhammer TR. Bacteriocins of lactic acid bacteria. Biochimie. 1988;70:337-349
  41. 41. Marty-Teysset C, De La Torre F, Garel JR. Increased production of hydrogen peroxide by Lactobacillus delbrueckii subsp. bulgaricus upon aeration: Involvement of an NADH oxidase in oxidative stress. Applied and Environmental Microbiology. 2000;66:262-267
  42. 42. Shokryazdan P, Sieo CC, Kalavathy R, Liang JB, Alitheen NB, Jahromi MF, et al. Probiotic potential of Lactobacillus strains with antimicrobial activity against some human pathogenic strains. BioMed Research International. 2014. DOI: 10.1155/2014/927268
  43. 43. Chen H, Hoover DG. Bacteriocins and their food applications. Comprehensive Reviews in Food Science and Food Safety. 2003;2:82-100
  44. 44. Pascual LM, Daniele MB, Giordano W, Pajaro MC, Barberis IL. Purification and partial characterization of novel bacteriocin L23 produced by Lactobacillus fermentum L23. Current Microbiology. 2008;56:397-402
  45. 45. Sharma A, Srivastava S. Anti-Candida activity of two-peptide bacteriocins, plantaricins (Pln E/F and J/K) and their mode of action. Fungal Biology. 2014;118:264-275
  46. 46. Okkers DJ, Dicks LMT, Silvester M, Joubert JJ, Odendaal HJ. Characterization of pentocin TV35b, a bacteriocin-like peptide isolated from Lactobacillus pentosus with a fungistatic effect on Candida albicans. Journal of Applied Microbiology. 1999;87:726-734
  47. 47. Calderone RA, Fonzi WA. Virulence factors of Candida albicans. Trends in Microbiology. 2001;9:327-335
  48. 48. Douglas LJ. Candida biofilm and their role in infection. Trends in Microbiology. 2003;11:30-36
  49. 49. Talarico TL, Casas IA, Chung TC, Dobrogosz WJ. Production and isolation of reuterin, a growth inhibitor produced by Lactobacillus reuteri. Antimicrobial Agents and Chemotherapy. 1988;32(12):1854-1858
  50. 50. Schütz H, Radler F. Anaerobic reduction of glycerol to propanediol-1.3 by Lactobacillus brevis and Lactobacillus buchneri. Systematic and Applied Microbiology. 1984;5(2):169-178
  51. 51. Claisse O, Lonvaud-Funel A. Assimilation of glycerol by a strain of Lactobacillus collinoides isolated from cider. Food Microbiology. 2000;17(5):513-519
  52. 52. Magnusson J, Ström K, Roos S, Sjögren J, Schnürer J. Broad and complex antifungal activity among environmental isolates of lactic acid bacteria. FEMS Microbiology Letters. 2003;219(1):129-135
  53. 53. Talarico TL, Dobrogosz WJ. Chemical characterization of an antimicrobial substance produced by Lactobacillus reuteri. Antimicrobial Agents and Chemotherapy. 1989;33:674-679
  54. 54. Schaefer L, Auchtung TA, Hermans KE, Whitehead D, Borhan B, Britton RA. The antimicrobial compound reuterin (3-hydroxypropionaldehyde) induces oxidative stress via interaction with thiol groups. Microbiology. 2010;156(6):1589-1599
  55. 55. Ganzle MG. Characterization of reutericyclin produced by Lactobacillus reuteri LTH2584. Applied and Environmental Microbiology. 2000;66:4325-4333
  56. 56. Jay JM. Antimicrobial properties of diacetyl. Applied and Environmental Microbiology. 1982;44(3):525-532
  57. 57. Chung TC, Axelsson L, Lindgren SE, Dobrogosz WJ. In vitro studies on reuterin synthesis by Lactobacillus reuteri. Microbial Ecology in Health and Diseases. 1989;2:137-144
  58. 58. Corey RB. Crystal structure of diketopiperazine. Journal of the American Chemical Society. 1938;60:1598-1604. DOI: 10.1021/ja01274a023
  59. 59. Martins MB, Carvalho I. Diketopiperazines: Biological activity and synthesis. Tetrahedron. 2007;63:9923-9932. DOI: 10.1016/j.tet.2007.04.105
  60. 60. Nicholson B. NPI-2358 is a tubulin-depolymerizing agent: In-vitro evidence for activity as a tumor vascular-disrupting agent. Anti-Cancer Drugs. 2006;17:25. DOI: 10.1097/01.cad.0000182745.01612.8a
  61. 61. Sinha S, Srivastava R, Clercq D, Erik, Singh RK. Synthesis and antiviral properties of arabino and ribonucleosides of 1,3-dideazaadenine, 4-nitro-1,3-dideazaadenine and diketopiperazine. Nucleosides, Nucleotides & Nucleic Acids. 2004;23(12):1815-1824. DOI: 10.1081/NCN-200040614
  62. 62. Houston DR, Synstad B, Eijsink VGH, Stark MJR, Eggleston IM, van Aalten DMF. Structure-based exploration of cyclic dipeptide chitinase inhibitors. Journal of Medicinal Chemistry. 2004;47(23):5713-5720. DOI: 10.1021/jm049940a
  63. 63. Kwon OS, Park SH, Yun B-S, Pyun YR, Kim C-J. Cyclo(dehydroala-L-Leu), an a-glucosidase inhibitor from Penicillium sp. F70614. The Journal of Antibiotics. 2000;53(9):954-958
  64. 64. Li H, Liu L, Zhang S, Cui W, Lv J. Identification of antifungal compounds produced by Lactobacillus casei AST18. Current Microbiology. 2012;65(2):156-161
  65. 65. Ström K, Sjögren J, Broberg A, Schnürer J. Lactobacillus plantarum MiLAB 393 produces the antifungal cyclic dipeptides cyclo (L-Phe-L-Pro) and cyclo (L-Phe-trans-4-OH-L-Pro) and 3-phenyllactic acid. Applied and Environmental Microbiology. 2002;68(9):4322-4327
  66. 66. Niku-Paavola ML, Laitila A, Mattila-Sandholm T, Haikara A. New types of antimicrobial compounds produced by Lactobacillus plantarum. Journal of Applied Microbiology. 1999;86(1):29-35
  67. 67. Li J, Wang W, Xu SX, Magarvey NA, McCormick JK. Lactobacillus reuteri-produced cyclic dipeptides quench agr-mediated expression of toxic shock syndrome toxin-1 in Staphylococci. Proceedings of the National Academy of Sciences. 2011;108(8):3360-3365
  68. 68. Ryan LA, Zannini E, Dal Bello F, Pawlowska A, Koehler P, Arendt EK. Lactobacillus amylovorus DSM 19280 as a novel food-grade antifungal agent for bakery products. International Journal of Food Microbiology. 2011;146(3):276-283
  69. 69. Yang EJ, Chang HC. Purification of a new antifungal compound produced by Lactobacillus plantarum AF1 isolated from Kimchi. International Journal of Food Microbiology. 2010;139(1-2):56-63
  70. 70. Japan Patent JP2018-070463A. Anti-bacterial agent containing cyclic dipeptide against periodontal pathogens; 2018
  71. 71. Banni S. Conjugated linoleic acid metabolism. Current Opinion in Lipidology. 2002;13(3):261-266
  72. 72. Sugano M, Tsujita A, Yamasaki M, Noguchi M, Yamada K. Conjugated linoleic acid modulates tissue levels of chemical mediators and immunoglobulins in rats. Lipids. 1998;33(5):521-527
  73. 73. Mazidi M, Karimi E, Rezaie P, Ferns GA. Effects of conjugated linoleic acid supplementation on serum C-reactive protein: A systematic review and meta-analysis of randomized controlled trials. Cardiovascular Therapeutics. 2017;35(6):e12275
  74. 74. Flemming HC, Wingender J. The biofilm matrix. Nature Reviews. Microbiology. 2010;8:623-633
  75. 75. Allison DG. The biofilm matrix. Biofouling. 2003;19:139-150
  76. 76. Wimpenny J. An overview of biofilms as functional communities. In: Allison D, Gilbert P, Lappin-Scott HM, Wilson M, editors. Society for General Microbiology Symposium. Community Structure and Co-operation in Biofilms, Vol. 59. Cambridge: Cambridge University Press; 2000
  77. 77. Sperandio V, Torres AG, Jarvis B, Nataro JP, Kaper JB. Bacteria–host communication: The language of hormones. Proceedings of the National Academy of Sciences. 2003;100(15):8951-8956
  78. 78. Liévin-Le Moal V, Servin AL. Anti-infective activities of Lactobacillus strains in the human intestinal microbiota: From probiotics to gastrointestinal anti-infectious biotherapeutic agents. Clinical Microbiology Reviews. 2014;27(2):167-199
  79. 79. Li J, Wang W, Xu SX, Magarvey NA, McCormick JK. Lactobacillus reuteri-produced cyclic dipeptides quench agr-mediated expression of toxic shock syndrome toxin-1 in staphylococci. Proceedings of the National Academy of Sciences. 2011;108(8):3360-3365

Written By

Tomoko Ohshima, Tomomi Kawai and Nobuko Maeda

Submitted: July 20th, 2019 Reviewed: August 3rd, 2019 Published: September 12th, 2019