Oral infectious diseases remain major challenges in modern Dentistry. Caries and periodontal diseases are considered to be the most prevalent diseases in the industrialized world. The major oral infectious diseases are caused by opportunistic pathogens, and Philip Marsh has reviewed (Microbiology 149:279-294, 2003) the basis for considering Dental infectious diseases as prime examples of ecological catastrophes. Disease occurs as a result of shifts, due to stress conditions, in oral biofilm communities; thereby, favoring organisms that possess so-called pathogenic personalities. For example, highly aciduric organisms or those with high capacities to induce inflammatory responses of the host might thrive under these conditions. The development of new types of antimicrobials, other than antibiotics, is currently perhaps the most promising approach for preventing and treating oral infectious diseases. We have shown that the formation of mono- unsaturated membrane fatty acids (UFAs) is important for the ability of S. mutans to survive acidic environments (Fozo and Quivey, 2004a and b). Further, we have shown that the formation of unsaturated fatty acids in S. mutans is dependent on a single enzyme, FabM (Fozo and Quivey, 2004b). We include more recent data in the Preliminary Studies section to show that loss of FabM dramatically lowers the ability of S. mutans to cause disease in rats. The FabM enzyme is presently identified in only 3 bacterial genera: the Streptococci. Staphylococci, and Fusobacteria. Thus, knowledge about the role of the enzyme in S. mutans will shed light on other important human pathogens. Nevertheless, we are currently lacking information regarding the regulation of membrane biosynthesis enzymes, and how those enzymes are used by S. mutans to control membrane homeostasis. Our hypothesis is that S. mutans regulates its membrane composition in response to external acidification in order to maintain homeostasis in membrane fluidity. We propose a series of experiments designed to complete our earlier work and to test our hypothesis. [Our goal is to achieve a thorough understanding of the S. mutans membrane biosynthesis during growth at low pH.
Our Specific Aims are as follows: 1) we will complete our biochemical characterization of pH-dependent changes in membranes, with the goal of measuring changes in phospholipids and branched chain fatty acids; 2) we will use biochemical and molecular tools to determine the mechanism of genetic regulation of fab genes and the role of fabR in regulating the fab gene cluster; 3) we will use biochemical and genetic tools to elucidate the relationship of FabM and FabK to membrane composition; 4) we will determine how pH-dependent changes in S. mutans membranes relate to fluidity; 5) finally, we will determine how S. mutans uses its fab genes to respond to membrane disrupting agents such as cerulenin and tt-farnesol. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE017157-03
Application #
7425406
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
2006-07-01
Project End
2011-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
3
Fiscal Year
2008
Total Cost
$357,306
Indirect Cost
Name
University of Rochester
Department
Dentistry
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Baker, J L; Faustoferri, R C; Quivey Jr, R G (2017) Acid-adaptive mechanisms of Streptococcus mutans-the more we know, the more we don't. Mol Oral Microbiol 32:107-117
Cross, Benjamin; Faustoferri, Roberta C; Quivey Jr, Robert G (2016) What are We Learning and What Can We Learn from the Human Oral Microbiome Project? Curr Oral Health Rep 3:56-63
Cross, Benjamin; Garcia, Ariana; Faustoferri, Roberta et al. (2016) PlsX deletion impacts fatty acid synthesis and acid adaptation in Streptococcus mutans. Microbiology 162:662-71
Quivey Jr, R G; Grayhack, E J; Faustoferri, R C et al. (2015) Functional profiling in Streptococcus mutans: construction and examination of a genomic collection of gene deletion mutants. Mol Oral Microbiol 30:474-95
Faustoferri, R C; Hubbard, C J; Santiago, B et al. (2015) Regulation of fatty acid biosynthesis by the global regulator CcpA and the local regulator FabT in Streptococcus mutans. Mol Oral Microbiol 30:128-46
Baker, J L; Abranches, J; Faustoferri, R C et al. (2015) Transcriptional profile of glucose-shocked and acid-adapted strains of Streptococcus mutans. Mol Oral Microbiol 30:496-517
Buckley, Andrew A; Faustoferri, Roberta C; Quivey Jr, Robert G (2014) ?-Phosphoglucomutase contributes to aciduricity in Streptococcus mutans. Microbiology 160:818-27
Santiago, Brendaliz; Marek, Maksym; Faustoferri, Roberta C et al. (2013) The Streptococcus mutans aminotransferase encoded by ilvE is regulated by CodY and CcpA. J Bacteriol 195:3552-62
MacGilvray, Matthew E; Lapek Jr, John D; Friedman, Alan E et al. (2012) Cardiolipin biosynthesis in Streptococcus mutans is regulated in response to external pH. Microbiology 158:2133-43
Santiago, Brendaliz; MacGilvray, Matthew; Faustoferri, Roberta C et al. (2012) The branched-chain amino acid aminotransferase encoded by ilvE is involved in acid tolerance in Streptococcus mutans. J Bacteriol 194:2010-9

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