Proteostasis-targeted antibacterial strategies

Area of Science:

• Microbiology
• Molecular Biology
• Drug Discovery

Background:

• Bacterial survival and antibiotic tolerance are linked to protein quality control systems.
• Conventional antibiotics face challenges due to bacterial adaptation and resistance.
• Targeting molecular chaperones and proteases presents a novel antibacterial strategy.

Purpose of the Study:

• To review the mechanistic basis of proteostasis-centered antibacterial strategies.
• To summarize recent developments in targeting bacterial protein quality control.
• To discuss the translational potential of these novel approaches.

Main Methods:

• Review of recent literature on proteostasis and antibacterial strategies.
• Analysis of molecular mechanisms involving chaperones and proteases.
• Evaluation of novel therapeutic modalities like small molecules, APPs, and BacPROTACs.

Main Results:

• Proteostasis-targeted approaches are effective against antibiotic-tolerant persister and VBNC cells.
• Strategies include modulating chaperone/protease activity, inducing proteotoxic stress, and using bacterial PROTACs.
• Combining proteostasis inhibitors with conventional antibiotics enhances bactericidal efficacy.

Conclusions:

• Proteostasis-centered strategies offer a promising avenue to combat bacterial infections and overcome antimicrobial resistance.
• These approaches are effective against both actively dividing and dormant bacterial populations.
• Further development holds potential for new antibacterial therapies.