Title |
Protein aggregation as an antibiotic design strategy
|
---|---|
Published in |
Molecular Microbiology, December 2015
|
DOI | 10.1111/mmi.13269 |
Pubmed ID | |
Authors |
Natalia G Bednarska, Johan van Eldere, Rodrigo Gallardo, Ashok Ganesan, Meine Ramakers, Isabel Vogel, Pieter Baatsen, An Staes, Marc Goethals, Per Hammarström, K Peter R Nilsson, Kris Gevaert, Joost Schymkowitz, Frederic Rousseau |
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 haematological 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
Belgium | 2 | 12% |
United Kingdom | 2 | 12% |
Turkey | 1 | 6% |
Netherlands | 1 | 6% |
South Africa | 1 | 6% |
Unknown | 10 | 59% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 9 | 53% |
Scientists | 8 | 47% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 1 | <1% |
Unknown | 102 | 99% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 19 | 18% |
Student > Ph. D. Student | 17 | 17% |
Student > Master | 13 | 13% |
Student > Bachelor | 12 | 12% |
Other | 7 | 7% |
Other | 14 | 14% |
Unknown | 21 | 20% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 27 | 26% |
Agricultural and Biological Sciences | 15 | 15% |
Medicine and Dentistry | 8 | 8% |
Chemistry | 8 | 8% |
Immunology and Microbiology | 7 | 7% |
Other | 17 | 17% |
Unknown | 21 | 20% |