Protein aggregation as an antibiotic design strategy

Mol Microbiol. 2016 Mar;99(5):849-65. doi: 10.1111/mmi.13269. Epub 2015 Dec 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / biosynthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Antimicrobial Cationic Peptides / biosynthesis
  • Antimicrobial Cationic Peptides / chemistry
  • Antimicrobial Cationic Peptides / genetics
  • Antimicrobial Cationic Peptides / pharmacology*
  • Bacteremia / drug therapy*
  • Bacterial Proteins / metabolism*
  • Drug Design
  • Female
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Methicillin-Resistant Staphylococcus aureus / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Protein Aggregates / drug effects*
  • Pseudomonas aeruginosa / drug effects
  • Pseudomonas aeruginosa / metabolism
  • Sepsis / therapy
  • Staphylococcal Infections / drug therapy
  • Staphylococcal Infections / microbiology


  • Anti-Bacterial Agents
  • Antimicrobial Cationic Peptides
  • Bacterial Proteins
  • Protein Aggregates