A rational approach to discovering new persister control agents

Area of Science:

• Microbiology
• Drug Discovery
• Computational Chemistry

Background:

• Conventional antibiotic discovery fails against dormant persister cells, leading to infection relapse.
• A new approach is required to develop agents that eradicate these resilient cells.
• Persistent infections are a significant unmet medical need.

Purpose of the Study:

• To discover novel compounds effective against dormant bacterial persister cells.
• To develop and apply a chemoinformatic clustering algorithm for identifying persister-targeting agents.
• To validate the efficacy of identified leads against clinically relevant bacteria and biofilms.

Main Methods:

• Utilized a tailored chemoinformatic clustering algorithm based on established principles for persister cell targeting.
• Screened a small compound library with known antimicrobial activity against normal bacterial cells.
• Conducted experimental validation of eleven clustered compounds against *Escherichia coli* persister cells.

Main Results:

• Identified five novel compounds capable of penetrating and eradicating *Escherichia coli* HM22 persister cells.
• Top lead compounds demonstrated activity against *Pseudomonas aeruginosa* and uropathogenic *E. coli* (UPEC) persister cells.
• Efficacy was also confirmed against UPEC biofilms and associated persister cells.

Conclusions:

• The developed chemoinformatic approach successfully identified potent agents against dormant persister cells.
• This rational drug discovery strategy holds significant promise for combating persistent infections.
• The findings offer a new avenue for developing treatments that address the root cause of relapsing infections.