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Project

Targeted Protein Aggregation as a Novel Antimicrobial Strategy.

 Peptide aggregates  are associated with human diseases , such as Alzheimer's and type II diabetes through loss of specific cell types due to their inherent cytotoxicity, suggesting that peptide-induced proteotoxic stress can be cell-type specific. Moreover the in vitro </>studies of protein aggregation suggest that the aggregation arise due to very specific intermolecular interactions among defined domains within structured folding intermediates. Specific short segments of amyloid-forming proteins have been
shown to form fibrils themselves and are able to seed and facilitate
incorporation of globular proteins into amyloid structures.
To test this hypothesis we designed synthetic aggregating peptides based on aggregation prone amino acid sequences in the proteome of S. epidermidis</>. We found
that a subset of these peptides displayed selective bactericidal activity both in
vitro</> as well as in an in vivo</> mouse sepsis model at concentrations
comparable to commonly used antibiotics and without apparent toxic or
haemolytic effects. We show thatthese peptides specifically accumulate inside
bacteria but not in mammalian cells and that their activity is non-lytic but
aggregation-dependent. Moreover their activity is sequence specific as
scrambled peptides are inactive against S. epidermidis. </>Proteomic
analysis revealed that these peptides trigger an aggregation cascade that
results in the proteostatic collapse of the bacterial proteome.
 This research highlighted the central importance of protein homeostasis, or proteostasis for short, defined as the cellular state in which the proteome is both stable and functional. It implicates equilibrium between synthesis,folding, trafficking, aggregation, disaggregation and degradation.
In conclusion this thesis work shows that the sequence specificity of aggregation can be harnessed to selectively target bacterial proteomes and generate novel and
versatile modes of antibiotic activity. This finding could be a breakthrough and hope for future treatment of nosocomial diseases, especially in the light of emerging multi drug resistant and pan resistant strains.  
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Date:1 Aug 2009 →  5 Dec 2013
Keywords:aggregation, protein
Disciplines:Microbiology, Systems biology, Laboratory medicine
Project type:PhD project