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High-throughput Screening of Chemical Compounds to Elucidate Their Effects on Bacterial Persistence
Published on: February 23, 2021
Persister control by leveraging dormancy associated reduction of antibiotic efflux
Sweta Roy1, Ali Adem Bahar1, Huan Gu1
1Department of Biomedical and Chemical Engineering, Syracuse University, Syracuse, New York, United States of America.
Abstract:
Persistent bacterial infections do not respond to current antibiotic treatments and thus present a great medical challenge. These conditions have been linked to the formation of dormant subpopulations of bacteria, known as persister cells, that are growth-arrested and highly tolerant to conventional antibiotics. Here, we report a new strategy of persister control and demonstrate that minocycline, an amphiphilic antibiotic that does not require active transport to penetrate bacterial membranes, is effective in killing Escherichia coli persister cells [by 70.8 ± 5.9% (0.53 log) at 100 μg/mL], while being ineffective in killing normal cells. Further mechanistic studies revealed that persister cells have reduced drug efflux and accumulate more minocycline than normal cells, leading to effective killing of this dormant subpopulation upon wake-up. Consistently, eravacycline, which also targets the ribosome but has a stronger binding affinity than minocycline, kills persister cells by 3 logs when treated at 100 μg/mL. In summary, the findings of this study reveal that while dormancy is a well-known cause of antibiotic tolerance, it also provides an Achilles' heel for controlling persister cells by leveraging dormancy associated reduction of drug efflux.
Insights
Minocycline effectively kills dormant persister cells, a major cause of persistent bacterial infections, by accumulating within them due to reduced drug efflux. This discovery offers a new strategy for combating antibiotic resistance.
Area of Science:
- Microbiology
- Infectious Diseases
- Pharmacology
Background:
- Persistent bacterial infections pose a significant clinical challenge due to antibiotic resistance.
- Dormant bacterial subpopulations, known as persister cells, are highly tolerant to conventional antibiotics.
- Persister cells are growth-arrested and contribute to treatment failure.
Purpose of the Study:
- To investigate a novel strategy for controlling bacterial persister cells.
- To evaluate the efficacy of minocycline against Escherichia coli persister cells.
- To elucidate the mechanism by which minocycline targets persister cells.
Main Methods:
- Treatment of Escherichia coli cultures with minocycline and eravacycline at 100 μg/mL.
- Quantification of persister cell killing.
- Analysis of drug efflux and intracellular accumulation in persister versus normal cells.
Main Results:
- Minocycline demonstrated significant killing of Escherichia coli persister cells (70.8 ± 5.9%).
- Persister cells exhibited reduced drug efflux and higher intracellular minocycline accumulation compared to normal cells.
- Eravacycline achieved a 3-log reduction in persister cells.
Conclusions:
- Dormancy in persister cells, while conferring tolerance, presents a vulnerability.
- Reduced drug efflux in dormant persister cells facilitates the accumulation of antibiotics like minocycline.
- This mechanism offers a promising therapeutic strategy for eliminating persister cells and overcoming persistent bacterial infections.
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