Multidrug resistant Staphylococcus aureus (e.g., methicillin resistant [MRSA]) and enterococci (e.g., vancomycin resistant [VRE]) emerged in the 1960's and 1980's, and are leading causes of life-threatening infection in the hospital - more recently also in the community. Critically, after 20 years of containment, vancomycin resistance moved from VRE to MRSA, creating VRSA, and there are now 10 well documented cases. The overall goal of this program project is to identify and develop new drugs for treating infections caused by VRSA and VRE. This will be conducted hand-in-hand with studies to understand the development and proliferation of resistance in the multidrug resistant microbes being targeted in this Subproject. Overarching Goals: Determine what genetic or biological events led to the breach of containment of vancomycin resistance in VRE and transfer to VRSA, and demonstrate the activity of new compounds against them, by discovering and examining: -a known genetic event (insertional inactivation of a plasmid borne postsegregational killing TA module), - unknown traits within the genomes of the 10 well documented VRSA strains, and the putative VRE donors coisolated with them, - genetic and metabolic compatibilities, that may have predisposed them to coexist in mixed infection or participate in vancomycin resistance transfer, and - the efficacy of compounds developed in this PPG against these highly multidrug resistant, hospital adapted strains By understanding the basis for transfer as well as the nature of these increasingly resistant strains, we will be better positioned to assess the threat of continued erosion of antibiotic sensitivity in leading causes of hospital and community infection in the US, and will be alert to the types of conditions that promote this transfer.

Public Health Relevance

MRSA infections are common, often invasive and life threatening. VRE are leading causes of hospital acquired infection. VRE now have donated vancomycin resistance to MRSA, creating VRSA refractor to this last line antibiotic. This research aims to understand these multidrug resistant strains and the resistance transmission, and assess the efficacy of novel compounds against them.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI083214-06
Application #
8531138
Study Section
Special Emphasis Panel (ZAI1-LG-M)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
6
Fiscal Year
2013
Total Cost
$371,902
Indirect Cost
$135,022
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
073825945
City
Boston
State
MA
Country
United States
Zip Code
02114
Qiao, Yuan; Lebar, Matthew D; Schirner, Kathrin et al. (2014) Detection of lipid-linked peptidoglycan precursors by exploiting an unexpected transpeptidase reaction. J Am Chem Soc 136:14678-81
Van Tyne, Daria; Gilmore, Michael S (2014) A delicate balance: maintaining mutualism to prevent disease. Cell Host Microbe 16:425-7
Van Tyne, Daria; Gilmore, Michael S (2014) Friend turned foe: evolution of enterococcal virulence and antibiotic resistance. Annu Rev Microbiol 68:337-56
Elsholz, Alexander K W; Wacker, Sarah A; Losick, Richard (2014) Self-regulation of exopolysaccharide production in Bacillus subtilis by a tyrosine kinase. Genes Dev 28:1710-20
Santa Maria Jr, John P; Sadaka, Ama; Moussa, Samir H et al. (2014) Compound-gene interaction mapping reveals distinct roles for Staphylococcus aureus teichoic acids. Proc Natl Acad Sci U S A 111:12510-5
Foulston, Lucy; Elsholz, Alexander K W; DeFrancesco, Alicia S et al. (2014) The extracellular matrix of Staphylococcus aureus biofilms comprises cytoplasmic proteins that associate with the cell surface in response to decreasing pH. MBio 5:e01667-14
Pukkila-Worley, Read; Feinbaum, Rhonda L; McEwan, Deborah L et al. (2014) The evolutionarily conserved mediator subunit MDT-15/MED15 links protective innate immune responses and xenobiotic detoxification. PLoS Pathog 10:e1004143
Sassoubre, Lauren M; Ramsey, Matthew M; Gilmore, Michael S et al. (2014) Transcriptional response of Enterococcus faecalis to sunlight. J Photochem Photobiol B 130:349-56
Varahan, Sriram; Harms, Nathan; Gilmore, Michael S et al. (2014) An ABC transporter is required for secretion of peptide sex pheromones in Enterococcus faecalis. MBio 5:e01726-14
Valentino, Michael D; McGuire, Abigail Manson; Rosch, Jason W et al. (2014) Unencapsulated Streptococcus pneumoniae from conjunctivitis encode variant traits and belong to a distinct phylogenetic cluster. Nat Commun 5:5411

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