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Persister cells: molecular mechanisms related to antibiotic tolerance
1Department of Biology, Northeastern University, Boston, MA 02115, USA. k.lewis@neu.edu
Abstract:
It is a given that new antibiotics are needed to combat drug-resistant pathogens. However, this is only a part of the need-we actually never had antibiotics capable of eradicating an infection. All pathogens produce a small subpopulation of dormant persister cells that are highly tolerant to killing by antibiotics. Once an antibiotic concentration drops, surviving persisters re-establish the population, causing a relapsing chronic infection. Persisters are especially significant when the pathogen is shielded from the immune system by biofilms, or in sites where the immune components are limited-in the nervous system, the stomach, or inside macrophages.Antibiotic treatment during a prolonged chronic infection of P. aeruginosa in the lungs of patients with cystic fibrosis selects for high-persister (hip) mutants. Similarly, treatment of oral thrush infection selects for hip mutants of C. albicans. These observations suggest a direct causality between persisters and recalcitrance of the disease. It appears that tolerance of persisters plays a leading role in chronic infections, while resistance is the leading cause of recalcitrance to therapy in acute infections. Studies of persister formation in E. coli show that mechanisms of dormancy are highly redundant. Isolation of persisters produced a transcriptome which suggests a dormant phenotype characterized by downregulation of energy-producing and biosynthetic functions. Toxin-antitoxin modules represent a major mechanism of persister formation. The RelE toxin causes dormancy by cleaving mRNA; the HipA toxin inhibits translation by phosphorylating elongation factor Ef-Tu, and the TisB toxin forms a membrane pore, leading to a decrease in pmf and ATP.
Insights
Pathogen persister cells, dormant and antibiotic-tolerant, cause chronic infections. Understanding these persister cells and their high-persister mutants is key to developing new treatments for relapsing diseases.
Area of Science:
- Microbiology
- Infectious Diseases
- Drug Discovery
Background:
- Antibiotics are crucial for combating pathogens, but fail to eradicate infections due to dormant persister cells.
- Persister cells are a subpopulation of pathogens highly tolerant to antibiotics, enabling chronic and relapsing infections.
- These persister cells are particularly significant in infections shielded by biofilms or in immune-privileged sites.
Purpose of the Study:
- To investigate the role of persister cells in the recalcitrance of chronic infections.
- To understand the mechanisms of persister cell formation and their contribution to treatment failure.
- To explore the selection of high-persister (hip) mutants during antibiotic treatment.
Main Methods:
- Analyzing the transcriptome of persister cells to identify dormancy mechanisms.
- Investigating the role of toxin-antitoxin modules in persister formation.
- Observing the selection of high-persister mutants in chronic infections of P. aeruginosa and C. albicans.
Main Results:
- Persister cells exhibit a dormant phenotype with downregulated energy and biosynthetic functions.
- Toxin-antitoxin modules, including RelE, HipA, and TisB, are major contributors to persister formation.
- Antibiotic treatment of chronic infections selects for high-persister mutants, indicating their role in treatment recalcitrance.
Conclusions:
- Persister cell tolerance is a leading factor in chronic infection recalcitrance, whereas resistance drives acute infection failure.
- Understanding persister cell dormancy mechanisms is essential for developing novel therapeutic strategies against persistent infections.
- Targeting persister cells and their formation pathways may offer a new approach to eradicate chronic bacterial and fungal infections.
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