Staphylococcus aureus is key pathogen involved in nosocomial infections, frequently due to biofilm formation on indwelling devices. Once biofilms grow on these surfaces they are difficult to eradicate because the constituent cells display increased resistance to many antibiotics. This, combined with the fact that a large percentage of S. aureus isolates identified in infections now harbor resistance genes against numerous antibiotics including methicillin and vancomycin (MRSA, VRSA), makes it clear that new ways of combating staphyloccocal biofilm-associated infections need to be developed. This subproject ofthe Harvard-wide collaborative project for new MRSA treatments is focused on the development of anti-biofilm agents that target staphyloccocal biofilms. We have recently discovered two distinct mechanisms for inhibiting biofilm formation in a broad range of organisms, including S. aureus. The first mechanism is based on the finding that bacteria organize many membrane-related processes in functional microdomains that involve unusual lipids, i.e. bacteria have lipid rafts akin to those is found in eukaryotic cells. Interfering with the synthesis of these usual lipids can lead to complete elimination of biofilm formation without a lethal effect on the cells. The second discovery is that bacteria produce D-amino acids late in the life cycle of a biofilm and that these amino acids are incorporated into the peptidoglycan with the consequence that cells are released from the biofilm matrix and the biofilm is thus disassembled. While these processes have been analyzed in detail in the bacterium Bacillus subtilis, little is known about the mechanisms by which lipid synthesis inhibitors or D-amino acids prevent biofilm formation in S. aureus. To this end, we propose to: 1) Identify the lipid raft fomiation pathway in S. aureus and determine the mechanism through which anti-lipid raft agents inhibit biofilm formation, and 2) Determine the molecular mechanism through which D-amino acids affect S. aureus biofilms.
The inherent resistance of most biofilms to the action of antibiotics make biofilm-related infections difficult to eradicate. Our research satisfies this important unmet need in treating S. aureus infections by developing agents that prevent biofilm formation or disassemble existing biofilms. These agents are non-lethal to bacteria and therefore have minimal risk of developed resistance, and they can be used in conjunction with existing antibiotics to eliminate S. aureus biofilm-related 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|
Showing the most recent 10 out of 51 publications