title: Protein aggregation as an antibiotic design strategy.
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.
authors.affiliation: Laboratory of Clinical Bacteriology and Mycology, Department of Microbiology and Immunology, KULeuven, Leuven, Belgium.|Switch Laboratory, VIB, Leuven, Belgium.
authors.forename: Natalia G
authors.initials: NG
authors.lastname: Bednarska
authors.affiliation: Laboratory of Clinical Bacteriology and Mycology, Department of Microbiology and Immunology, KULeuven, Leuven, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: van Eldere
authors.affiliation: Switch Laboratory, VIB, Leuven, Belgium.|Switch Laboratory, Department of Cellular and Molecular Medicine, KULeuven, Leuven, Belgium.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Gallardo
authors.affiliation: Switch Laboratory, VIB, Leuven, Belgium.|Switch Laboratory, Department of Cellular and Molecular Medicine, KULeuven, Leuven, Belgium.
authors.forename: Ashok
authors.initials: A
authors.lastname: Ganesan
authors.affiliation: Switch Laboratory, VIB, Leuven, Belgium.|Switch Laboratory, Department of Cellular and Molecular Medicine, KULeuven, Leuven, Belgium.
authors.forename: Meine
authors.initials: M
authors.lastname: Ramakers
authors.affiliation: Laboratory of Immunology, Department of Microbiology and Immunology, KULeuven, Leuven, Belgium.
authors.forename: Isabel
authors.initials: I
authors.lastname: Vogel
authors.affiliation: Department of Molecular and Developmental Genetics (VIB11 and KULeuven), Electron Microscopy Network (EMoNe), Gasthuisberg, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Baatsen
authors.affiliation: Department of Medical Protein Research, VIB, Ghent, Belgium.|Department of Biochemistry, Ghent University, Ghent, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Staes
authors.affiliation: Department of Medical Protein Research, VIB, Ghent, Belgium.|Department of Biochemistry, Ghent University, Ghent, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Goethals
authors.affiliation: Department of Chemistry, Linköping University, Linköping, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Hammarström
authors.affiliation: Department of Chemistry, Linköping University, Linköping, Sweden.
authors.forename: K Peter R
authors.initials: KP
authors.lastname: Nilsson
authors.affiliation: Department of Medical Protein Research, VIB, Ghent, Belgium.|Department of Biochemistry, Ghent University, Ghent, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Gevaert
authors.affiliation: Switch Laboratory, VIB, Leuven, Belgium.|Switch Laboratory, Department of Cellular and Molecular Medicine, KULeuven, Leuven, Belgium.
authors.forename: Joost
authors.identifier: http://orcid.org/0000-0003-2020-0168
authors.initials: J
authors.lastname: Schymkowitz
authors.affiliation: Switch Laboratory, VIB, Leuven, Belgium.|Switch Laboratory, Department of Cellular and Molecular Medicine, KULeuven, Leuven, Belgium.
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D016470:Bacteremia / Q000188:drug therapy*; D001426:Bacterial Proteins / Q000378:metabolism*; D015195:Drug Design; D005260:Female; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D066329:Protein Aggregates / Q000187:drug effects*; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000378:metabolism; D018805:Sepsis / Q000628:therapy; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001426:Bacterial Proteins; D066329:Protein Aggregates