Protein aggregation as an antibiotic design strategy

Area of Science:

• Microbiology
• Biochemistry
• Drug Discovery

Background:

• Bacterial infections pose a significant threat, necessitating novel therapeutic strategies.
• Targeting pathogen-specific mechanisms, like protein aggregation, offers a potential avenue for selective antimicrobial action.
• Exploiting the xenobiotic nature of bacteria is key to developing treatments that spare host cells.

Purpose of the Study:

• To investigate the potential of using aggregation-prone peptide sequences from bacterial proteomes to induce toxic protein aggregation specifically within bacterial pathogens.
• To assess the antimicrobial activity and host safety of these identified peptides.
• To explore a new chemical space for developing novel antimicrobial therapies.

Main Methods:

• In vitro screening of bacterial genome-derived peptide sequences for aggregation propensity and bactericidal activity.
• In vivo testing of identified peptides in a mouse model of bacterial sepsis.
• Histological and hematological evaluations to assess in vivo toxicity.
• Microscopic analysis to determine peptide localization and mechanism of action within bacterial cells.

Main Results:

• Identification of several peptides exhibiting strong bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA).
• Successful treatment of bacterial sepsis in mice upon parenteral administration of these peptides.
• Absence of apparent toxic side effects in treated mice, confirmed by histological and hematological analyses.
• Demonstration that peptides enter and accumulate in the bacterial cytosol, inducing bacterial polypeptide aggregation.

Conclusions:

• Peptides derived from aggregation-prone bacterial protein sequences can selectively induce toxic protein aggregation in bacteria, leading to cell death.
• This approach represents a promising, unexplored strategy for developing novel antimicrobial agents against challenging bacterial pathogens.
• The identified peptides demonstrate therapeutic potential for treating bacterial infections, including sepsis, with a favorable safety profile.