Enterococcus faecalis is a major cause of hospital-acquired infections and also plays a key role in the dissemination of antibiotic resistance and virulence genes to other bacterial pathogens. This application seeks continued support for basic studies of a unique peptide-based signaling system that allows cells carrying an antibiotic resistance/virulence plasmid called pCF10 to regulate expression of genes involved in resistance transfer and virulence. The key players in the signaling system include the cCF10 peptide pheromone (signal molecule) and the iCF10 peptide pheromone inhibitor which antagonizes cCF10. The receptor for these peptides is a transcription factor called PrgX, which regulates expression of the pCF10 prgQ operon encoding the virulence and plasmid transfer genes. The pheromone response machinery comprises a sensitive and robust biological switch, where multiple regulatory circuits act in concert to amplify the direct response to pheromone, and to enable the host cell to sense different kinds of environmental cues. Post-transcriptional regulatory mechanisms involving novel small RNAs also play a major role in the pheromone response. The proposed studies are focused on elucidating the quantitative effects mechanistic aspects of various regulatory circuits, and on determining the mechanisms by which the pheromone-induced state can be returned to basal levels of expression following transfer of the plasmid to a new host. This work will reveal insights into regulation of microbial virulence by cell-cell signaling, applicable to many organisms, and may also facilitate new strategies for development of antimicrobial agents.

Public Health Relevance

This research investigates the process by which bacteria communicate with one another using small molecule signals. In this case the signal causes cells carrying antibiotic resistance genes to transfer copies of these genes to other cells. The bacterial species involved is Enterococcus faecalis and the transfer process increases the virulence and antibiotic resistance of strains that cause infections in hospitals. The basic knowledge gained from this research may provide new insights into the development of more effective forms of antimicrobial chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM049530-29
Application #
8514623
Study Section
Special Emphasis Panel (ZRG1-GGG-F (02))
Program Officer
Sledjeski, Darren D
Project Start
1992-09-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
29
Fiscal Year
2013
Total Cost
$298,211
Indirect Cost
$76,861
Name
University of Minnesota Twin Cities
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Dunny, Gary M; Berntsson, Ronnie Per-Arne (2016) Enterococcal Sex Pheromones: Evolutionary Pathways to Complex, Two-Signal Systems. J Bacteriol 198:1556-62
Borrero, Juan; Chen, Yuqing; Dunny, Gary M et al. (2015) Modified lactic acid bacteria detect and inhibit multiresistant enterococci. ACS Synth Biol 4:299-306
Bhatty, Minny; Cruz, Melissa R; Frank, Kristi L et al. (2015) Enterococcus faecalis pCF10-encoded surface proteins PrgA, PrgB (aggregation substance) and PrgC contribute to plasmid transfer, biofilm formation and virulence. Mol Microbiol 95:660-77
Johnson, Christopher M; Chen, Yuqing; Lee, Heejin et al. (2014) Identification of a conserved branched RNA structure that functions as a factor-independent terminator. Proc Natl Acad Sci U S A 111:3573-8
Cook, Laura C C; Dunny, Gary M (2014) The Influence of Biofilms in the Biology of Plasmids. Microbiol Spectr 2:
Cook, Laura C C; Dunny, Gary M (2014) The influence of biofilms in the biology of plasmids. Microbiol Spectr 2:0012
Chatterjee, Anushree; Cook, Laura C C; Shu, Che-Chi et al. (2013) Antagonistic self-sensing and mate-sensing signaling controls antibiotic-resistance transfer. Proc Natl Acad Sci U S A 110:7086-90
Dunny, Gary M (2013) Enterococcal sex pheromones: signaling, social behavior, and evolution. Annu Rev Genet 47:457-82
Berntsson, Ronnie P-A; Schuurman-Wolters, Gea K; Dunny, Gary et al. (2012) Structure and mode of peptide binding of pheromone receptor PrgZ. J Biol Chem 287:37165-70
Caserta, Enrico; Haemig, Heather A H; Manias, Dawn A et al. (2012) In vivo and in vitro analyses of regulation of the pheromone-responsive prgQ promoter by the PrgX pheromone receptor protein. J Bacteriol 194:3386-94

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