Replacement therapy has been shown to work successfully in rodents for the prevention of dental caries. This application describes studies designed to develop replacement therapy for the prevention of dental caries in humans. The purpose of Aims 1 and 2 is to further understand the physiology and ecological parameters of Streptococcus mutans in order to construct an effector strain that is both non-virulent and capable of efficiently colonizing the human oral cavity. These studies will involve accurate analysis of the fermentation patterns of wild-type and lactate dehydrogenase-deficient S. mutans, and identification of heritable changes that occur during prolonged colonization of the human oral cavity which help to adapt S. mutans to that environment. From the information obtained, idealized effector strains will be isolated. They will be tested in Aim 3, using gnotobiotic and conventional rat models, for their cariogenic potential. The ability of the effector strains to preemptively colonize the oral cavities of rodents, and displace indigenous strains of S. mutans will be tested in Aim 4. A strain of S. mutans that produces an unusually potent bacteriocin will serve as the starting strain for these studies.
In Aim 5 the minimum infection regimen required to obtain high levels of colonization by this strain in humans will be examined in a clinical pilot study involving 3 subjects. Microbiological analysis of saliva and plaque from these subjects will be used to determine the effects of the effector strain on indigenous S. mutans populations and on the general plaque microflora. The bacteriocin produced by this strain of S. mutans is of interest as a topical anti-caries agent.
In Aim 6, methods for its purification, sequencing, and in vitro synthesis are developed, using both conventional biochemical and recombinant DNA technology.
Aim 7 involves studies to directly demonstrate the role of the bacteriocin an an ecological determinant. The bacteriocin will also be tested in a rodent model for its ability to serve as a topical anti-caries agent.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Oral Biology and Medicine Study Section (OBM)
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Forsyth Institute
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Hillman, J D; McDonell, E; Cramm, T et al. (2009) A spontaneous lactate dehydrogenase deficient mutant of Streptococcus rattus for use as a probiotic in the prevention of dental caries. J Appl Microbiol 107:1551-8
Smith, Leif; Zachariah, Cherian; Thirumoorthy, Ramanan et al. (2003) Structure and dynamics of the lantibiotic mutacin 1140. Biochemistry 42:10372-84
Wu, Yi; Lee, Seok-Woo; Hillman, Jeffrey D et al. (2002) Identification and testing of Porphyromonas gingivalis virulence genes with a pPGIVET system. Infect Immun 70:928-37
Hillman, J D; Brooks, T A; Michalek, S M et al. (2000) Construction and characterization of an effector strain of Streptococcus mutans for replacement therapy of dental caries. Infect Immun 68:543-9
Smith, L; Novak, J; Rocca, J et al. (2000) Covalent structure of mutacin 1140 and a novel method for the rapid identification of lantibiotics. Eur J Biochem 267:6810-6
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Gutierrez, J A; Crowley, P J; Cvitkovitch, D G et al. (1999) Streptococcus mutans ffh, a gene encoding a homologue of the 54 kDa subunit of the signal recognition particle, is involved in resistance to acid stress. Microbiology 145 ( Pt 2):357-66
Hillman, J D; Novak, J; Sagura, E et al. (1998) Genetic and biochemical analysis of mutacin 1140, a lantibiotic from Streptococcus mutans. Infect Immun 66:2743-9
Crowley, P J; Gutierrez, J A; Hillman, J D et al. (1997) Genetic and physiologic analysis of a formyl-tetrahydrofolate synthetase mutant of Streptococcus mutans. J Bacteriol 179:1563-72
Hillman, J D (1996) Principles of microbial ecology and their application to xerostomia-associated opportunistic infections of the oral cavity. Adv Dent Res 10:66-8

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