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Updated: Sep 13, 2025
High-throughput Screening of Chemical Compounds to Elucidate Their Effects on Bacterial Persistence
Published on: February 23, 2021
A rational approach to discovering new persister control agents
Sweta Roy1, Zeynep S Cakmak1, Sheila Priscilla Kyeremeh1
1Department of Biomedical and Chemical Engineering, Syracuse University, Syracuse, New York, USA.
Abstract:
Conventional antibiotic drug discovery selects leads based on bacterial growth inhibition. This approach is ineffective against growth-arrested persister cells. When the treatment stops, persister cells revert to normal cells, causing the infection to relapse. To address the challenge of persistent infections, a paradigm shift in antibiotic development is needed to identify new leads that can eradicate dormant cells. Based on our foundational study, we recently proposed a set of principles for developing new persister killing agents. Here, we report the discovery of new leads that are effective against persister cells using a tailored chemoinformatic clustering algorithm based on these principles. We focused on persister penetration using a small compound library that has known antimicrobial activities against normal cells. Experimental testing of eleven compounds identified from clustering led to the discovery of five new compounds that can effectively penetrate and kill persister cells of Escherichia coli HM22. The top leads were further tested and also found active against persister cells of Pseudomonas aeruginosa and uropathogenic E. coli (UPEC), as well as UPEC biofilms and biofilm-associated persister cells. This rather high yield demonstrates the potential of this new rational approach in identifying effective agents against dormant cells, a root cause of persistent infections that is largely missed in conventional screening.
Insights
New drug discovery methods are needed to target dormant bacterial persister cells, which cause infections to relapse. This study identifies novel compounds effective against these resilient cells, offering hope for treating persistent infections.
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.
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