Protein aggregation as an antibiotic design strategy
| Autor: | Isabel Vogel, Rodrigo Gallardo, Johan Van Eldere, An Staes, Natalia G. Bednarska, Marc Goethals, Pieter Baatsen, Kris Gevaert, Meine Ramakers, Frederic Rousseau, Joost Schymkowitz, Ashok Ganesan, Per Hammarström, K. Peter R. Nilsson |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
biology Antimicrobial peptides Bacterial genome size Protein aggregation Staphylococcal infections medicine.disease Antimicrobial biology.organism_classification Microbiology 3. Good health 03 medical and health sciences 030104 developmental biology Biochemistry Chaperone (protein) medicine biology.protein Molecular Biology Bacterial morphological plasticity Bacteria |
| Zdroj: | Molecular Microbiology. 99:849-865 |
| ISSN: | 0950-382X |
| DOI: | 10.1111/mmi.13269 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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