Abstract
There are many examples of positive and negative interactions between different species of bacteria inhabiting the same ecosystem. This observation provides the basis for a novel approach to preventing microbial diseases called replacement therapy. In this approach, a harmless effector strain is permanently implanted in the host's microflora. Once established, the presence of the effector strain prevents the colonization or outgrowth of a particular pathogen. In the case of dental caries, replacement therapy has involved construction of an effector strain called BCS3-L1, which was derived from a clinical Streptococcus mutans isolate. Recombinant DNA technology was used to delete the gene encoding lactate dehydrogenase in BCS3-L1 making it entirely deficient in lactic acid production. This effector strain was also designed to produce elevated amounts of a novel peptide antibiotic called mutacin 1140 that gives it a strong selective advantage over most other strains of S. mutans. In laboratory and rodent model studies, BCS3-L1 was found to be genetically stable and to produce no apparent deleterious side effects during prolonged colonization. BCS3-L1 was significantly less cariogenic than wild-type S. mutansin gnotobiotic rats, and it did not contribute at all to the cariogenic potential of the indigenous flora of conventional Sprague-Dawley rats. And, its strong colonization properties indicated that a single application of the BCS3-L1 effector strain to human subjects should result in its permanent implantation and displacement over time of indigenous, disease-causing S. mutans strains. Thus, BCS3-L1 replacement therapy for the prevention of dental caries is an example of biofilm engineering that offers the potential for a highly efficient, cost effective augmentation of conventional prevention strategies. It is hoped that the eventual success of replacement therapy for the prevention of dental caries will stimulate the use of this approach in the prevention of other bacterial diseases.
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References
Abbe K, Takahashi S& Yamada T (1982) Involvement of oxygensensitive pyruvate formate-lyase in mixed-acid fermentation by Streptococcus mutans under strictly anaerobic conditions. J. Bacteriol 152: 175–182.
Alaluusua S (1991) Transmission of mutans streptococci. Proc. Finnish Dent. Soc. 87: 443–447.
Anderson MH (1992) Changing paradigms in caries management. Curr. Opin. Dent. March: 2157–2162.
Berkowitz RJ& Jones P (1985) Mouth-to-mouth transmission of the bacterium Streptococcus mutans between mother and child. Arch. Oral Biol. 30: 377–379.
Blair EB& Tull AH (1969) Multiple infections among newborns resulting from colonization with Staphylococcus aureus 502A. Amer. J. Clin. Path. 52: 42–49.
Carlsson J, Kujala U& Edlund M-BK (1985) Pyruvate dehydrogenase activity in Streptococcus mutans. Infect. Immun. 49: 674–678.
Caufield PW& Walker TM (1989) Genetic diversity within Streptococcus mutans evident from chromosomal DNA restriction fragment polymorphisms J. Clin. Microbiol. 27: 274–278.
Chen A, Hillman JD& Duncan M (1994) L(+)-lactate dehydrogenase deficiency is lethal in Streptococcus mutans. J. Bacteriol. 176: 1542–1545.
Costerton JW (1995) Overview of microbial biofilms. J. Indust. Microbiol. 15: 137–140.
Crowe CC& Sanders Jr ES (1973) Bacterial interference II. Role of the normal throat flora in prevention of colonization by group A streptococcus. J. Infect. Dis. 128: 527–532.
Davey AL& Rogers AH (1984) Multiple types of the bacterium Streptococcus mutans in the human mouth and their intra-family transmission. Arch. Oral Biol. 29: 453–460.
Drutz DJ, van Way MH, Schaffner W& Koenig MG (1966) Bacterial interference in the therapy of recurrent staphylococcal infections: multiple abscesses due to implantation of the 502A strain of staphylococcus. New Eng. J. Med. 275: 1161–1165.
Duncan MJ& Hillman JD (1991) DNA sequence and in vitro mutagenesis of the gene encoding the fructose-1,6-diphosphatedependent L-(+)-lactate dehydrogenase of Streptococcus mutans. Infect. Immun. 59: 3930–3934.
Florey HW (1946) The use of micro-organisms for therapeutic purposes. Yale J. Biol. Med. 19: 101–117.
Fujimori I, Kikushima K, Hisamatsu K, Nozawa I, Goto R& Murakami Y (1997) Interaction between oral alpha-streptococci and group A streptococci in patients with tonsillitis. Ann. Oto. Rhino. Laryng. 106: 571–574.
Genco RJ& Loos BG (1991) The use of genomic DNA fingerprinting in studies of the epidemiology of bacteria in periodontitis. J. Clin. Periodont. 18: 396–405.
Hillman JD, Johnson KP& Yaphe BI (1984) Isolation of a Streptococcus mutans strain producing a novel bacterioc. Infect. Immun. 44: 141–144.
Hillman JD, Yaphe BI& Johnson KP (1985) Colonization of the human oral cavity by a strain of Streptococcus mutans. J. Dent. Res. 64: 1272–1274.
Hillman JD, Andrews SW& Dzuback AL (1987a) Acetoin production by wild-type strains and a lactate dehydrogenase-deficient mutant of Streptococcus mutans. Infect. Immun. 55: 1399–1402.
Hillman JD, Dzuback AL& Andrews SW (1987b) Colonization of the human oral cavity by a Streptococcus mutans mutant producing increased bacteriocin. J. Dent. Res. 66: 1092–1094.
Hillman JD, Andrews SW, Painter S& Stashenko P (1989) Adaptive changes in a strain of Streptococcus mutans during colonization of the human oral cavity. Microb. Ecol. Hlth. Dis. 2: 231–239.
Hillman JD, Duncan MJ& Stashenko KP (1990) Cloning and expression of the gene encoding the fructose-1,6-diphosphatedependent L-(+)-lactate dehydrogenase of Streptococcus mutans. Infect. Immun. 58: 1290–1295.
Hillman JD, Chen A, Duncan M& Lee S-W (1994) Evidence that L(+)-lactate dehydrogenase deficiency is lethal in Streptococcus mutans. Infect. Immun. 62: 60–64.
Hillman JD, Chen A& Snoep JL (1996) Genetic and physiological analysis of the lethal effect of L-(+)-lactate dehydrogenase deficiency in Streptococcus mutans: complementation by alcohol dehydrogenase from Zymomonas mobilis. Infect. Immun. 64: 4319–4323.
Hillman JD, Novak J, Sagura E, Gutierrez JA, Brooks TA, Crowley PJ, Azziz A, Leung K-P, Cvitkovitch D& Bleiweis AS (1998) Genetic and biochemical analysis of mutacin 1140, a lantibiotic from Streptococcus mutans. Infect. Immun. 66: 2743–2749.
Hillman JD, Brooks T, Michalek SM, Harmon CC& Snoep JL (2000) Construction and characterization of an effector strain of Streptococcus mutans for replacement therapy of dental caries. J. Dent. Res. 68: 543–549.
Houck PW, Nelson JD& Kay JL (1972) Fatal septicemia due to Staphylococcus aureus 502A. Amer. J. Dis. Child. 123: 45–48.
Hurst A (1981) Nisin. In: Perlman and Laskin (Eds) Advances in Applied Microbiology Vol. 27 (pp 85–123). Academic Press, London.
Johnson CP, Gross SM& Hillman JD (1980) Cariogenic potential in vitro in man and in vivo in the rat of lactate dehydrogenase mutants of Streptococcus mutans. Arch. Oral Biol. 25: 707–713.
Jordan HV, Englander HR, theEngler WO& Kulczyk S (1972) Observations on implantation and transmission of Streptococcus mutans in humans. J. Dent. Res. 51: 515–518.
Krasse B, Edwardsson S, Svensson I& Trell L (1967) Implantation of caries-inducing streptococci in the human oral cavity. Arch. Oral Biol. 12: 231–236.
Li Y-H, Lau PCY, Lee JH, Ellen R& Cvitkovitch DG (2001) Natural genetic transformation of Streptococcus mutans growing in biofilms. J. Bacteriol. 183: 897–908.
Light IJ, Walton L, Sutherland JM, Shinefield HR& Brackvogel V (1967) Use of bacterial interference to control a staphylococcal nursery outbreak: deliberate colonization of all infants with the 502A strain of Staphylococcus aureus. Amer. J. Dis. Child. 113: 291–300.
Perl TM& Golub JE (1998) New approaches to reduce Staphylococcus aureus nosocomial infection rates: treating S. aureus nasal carriage. Ann. Pharmacother. 32: S7–16.
Perry D& Kuramitsu HK (1981) Genetic transformation of Streptococcus mutans. Infect. Immun. 32: 1295–1297.
Ruangsri P& Orstavik D (1977) Effect of the acquired pellicle and of dental plaque on the implantation of Streptococcus mutans on tooth surfaces in man. Caries Res. 11: 204–210.
Sanders E (1969) Bacterial interference I. Its occurrence among the respiratory tract flora and characterization of inhibition of group A streptococci by viridans streptococci. J. Infect. Dis. 120: 698–707.
Sanders CC, Sanders WE& Harrowe DJ (1976) Bacterial interference: effects of oral antibiotics on the normal throat flora and its ability to interfere with group A streptococci. Infect. Immun. 13: 808–812.
Shinefield HR, Ribble JC& Boris M (1971) Bacterial interference between strains of Staphylococcus aureus, 1960 to 1970. Amer. J. Dis. Child. 121: 148–152.
Sprunt K, Leidy G& Redman W (1980) Abnormal colonization of neonates in an ICU: conversion to normal colonization by pharyngeal implantation of alpha hemolytic streptococcus strain 215. Ped. Res. 14: 308–313.
Sprunt K& Leidy G (1988) The use of bacterial interference to prevent infection. Can. J. Microbiol. 34: 332–338.
Stashenko KP& Hillman JD (1989) Microflora of plaque in rats following infection with an LDH-deficient mutant of Streptococcus mutans. Caries Res. 23: 375–377.
Svanberg M& Krasse B (1981) Oral implantation of saliva-treated Streptococcus mutans in man. Arch. Oral Biol. 26: 197–201.
Takahashi S, Abbe K& Yamada T (1982) Purification of pyruvate formate-lyase from Streptococcus mutans and its regulatory properties. J. Bacteriol. 149: 1034–1040.
Westergren G& Emilson CG (1983) Prevalence of transformable Streptococcus mutans in human dental plaque. Infect. Immun. 41: 1386–1388.
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Hillman, J.D. Genetically modified Streptococcus mutans for the prevention of dental caries. Antonie Van Leeuwenhoek 82, 361–366 (2002). https://doi.org/10.1023/A:1020695902160
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DOI: https://doi.org/10.1023/A:1020695902160