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Protein aggregation as an antibiotic design strategy

(2016) MOLECULAR MICROBIOLOGY. 99(5). p.849-865
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Abstract
Taking advantage of the xenobiotic nature of bacterial infections, we tested whether the cytotoxicity of protein aggregation can be targeted to bacterial pathogens without affecting their mammalian hosts. In particular, we examined if peptides encoding aggregation-prone sequence segments of bacterial proteins can display antimicrobial activity by initiating toxic protein aggregation in bacteria, but not in mammalian cells. Unbiased in vitro screening of aggregating peptide sequences from bacterial genomes lead to the identification of several peptides that are strongly bactericidal against methicillin-resistant Staphylococcus aureus. Upon parenteral administration in vivo, the peptides cured mice from bacterial sepsis without apparent toxic side effects as judged from histological and hematological evaluation. We found that the peptides enter and accumulate in the bacterial cytosol where they cause aggregation of bacterial polypeptides. Although the precise chain of events that leads to cell death remains to be elucidated, the ability to tap into aggregation-prone sequences of bacterial proteomes to elicit antimicrobial activity represents a rich and unexplored chemical space to be mined in search of novel therapeutic strategies to fight infectious diseases.
Keywords
CELLS, POLYPEPTIDES, BACTERIAL, RESISTANCE, MECHANISM, MEMBRANE, ALZHEIMERS-DISEASE, ANTIMICROBIAL PEPTIDES, AMYLOID-BETA-PROTEIN, PROPAGATION

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Chicago
Bednarska, Natalia G, Johan van Eldere, Rodrigo Gallardo, Ashok Ganesan, Meine Ramakers, Isabel Vogel, Pieter Baatsen, et al. 2016. “Protein Aggregation as an Antibiotic Design Strategy.” Molecular Microbiology 99 (5): 849–865.
APA
Bednarska, N. G., van Eldere, J., Gallardo, R., Ganesan, A., Ramakers, M., Vogel, I., Baatsen, P., et al. (2016). Protein aggregation as an antibiotic design strategy. MOLECULAR MICROBIOLOGY, 99(5), 849–865.
Vancouver
1.
Bednarska NG, van Eldere J, Gallardo R, Ganesan A, Ramakers M, Vogel I, et al. Protein aggregation as an antibiotic design strategy. MOLECULAR MICROBIOLOGY. 2016;99(5):849–65.
MLA
Bednarska, Natalia G, Johan van Eldere, Rodrigo Gallardo, et al. “Protein Aggregation as an Antibiotic Design Strategy.” MOLECULAR MICROBIOLOGY 99.5 (2016): 849–865. Print.
@article{7222638,
  abstract     = {Taking advantage of the xenobiotic nature of bacterial infections, we tested whether the cytotoxicity of protein aggregation can be targeted to bacterial pathogens without affecting their mammalian hosts. In particular, we examined if peptides encoding aggregation-prone sequence segments of bacterial proteins can display antimicrobial activity by initiating toxic protein aggregation in bacteria, but not in mammalian cells. Unbiased in vitro screening of aggregating peptide sequences from bacterial genomes lead to the identification of several peptides that are strongly bactericidal against methicillin-resistant Staphylococcus aureus. Upon parenteral administration in vivo, the peptides cured mice from bacterial sepsis without apparent toxic side effects as judged from histological and hematological evaluation. We found that the peptides enter and accumulate in the bacterial cytosol where they cause aggregation of bacterial polypeptides. Although the precise chain of events that leads to cell death remains to be elucidated, the ability to tap into aggregation-prone sequences of bacterial proteomes to elicit antimicrobial activity represents a rich and unexplored chemical space to be mined in search of novel therapeutic strategies to fight infectious diseases.},
  author       = {Bednarska, Natalia G and van Eldere, Johan and Gallardo, Rodrigo and Ganesan, Ashok and Ramakers, Meine and Vogel, Isabel and Baatsen, Pieter and Staes, An and Goethals, Marc and Hammarstr{\"o}m, Per and Nilsson, K Peter R and Gevaert, Kris and Schymkowitz, Joost and Rousseau, Frederic},
  issn         = {0950-382X},
  journal      = {MOLECULAR MICROBIOLOGY},
  language     = {eng},
  number       = {5},
  pages        = {849--865},
  title        = {Protein aggregation as an antibiotic design strategy},
  url          = {http://dx.doi.org/10.1111/mmi.13269},
  volume       = {99},
  year         = {2016},
}

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