Antibiotic resistant bacterial infections have become a major problem worldwide. Among Gram positive pathogens, invasive methicillin-resistant Staphylococcus aureus infections (MRSA) and vancomycinresistant enterococcal (VRE) infections represent particular threats. This proposal is a subproject in a Harvard-wide program to address the need to develop new approaches to overcome these infections. The four aims in this subproject are directed towards exploring new compounds, targets, and strategies to overcome MRSA and VRE.
The first aim i s to develop combined chemical and enzymatic methods to make novel phosphoglycolipid antibiotics that inhibit peptidoglycan (PG) biosynthesis by targeting the enzymes that make the glycan chains of PG.
The second aim i s to elucidate the pathway for wall teichoic acid (WTA) biosynthesis in Enterococcus faecalis and assess its potential as an antibacterial target in order to lay the groundwork for inhibitor screening.
The third aim i s to discover novel TarO inhibitors that can be used in combination with beta lactams to overcome MRSA infections.
The fourth aim, to be carried out in collaboration with other subprojects, is to evaluate the compounds we discover in prioritized animal models. These studies will include evaluation of a 8. aureus-selective WTA-active antibiotic that we previously discovered and have already optimized for in vitro activity. The proposed research may lead to the development of new antibiotics for clinical use to treat MRSA and VRE infections.
Antibiotic resistant bacterial infections have become a major problem worldwide. Among Gram positive pathogens, invasive methicillin-resistant Staphylococcus aureus infections (MRSA) and vancomycin-resistant enterococcal (VRE) infections represent particular threats. The proposed work addresses the need to develop new approaches to overcome these infections.
|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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