Bacterial Persistence Mechanisms and Antibiotic Tolerance

Bacterial persistence describes a transient, non-inherited state in which a small subpopulation of cells survives lethal antibiotic exposure without acquiring genetic resistance. Persisters exhibit profound metabolic slowdown or dormancy, rendering antibiotic targets inactive. Multiple pathways converge on this state, including toxin–antitoxin modules that inhibit essential processes, accumulation of the alarmone (p)ppGpp triggering the stringent response, stochastic drops in cellular ATP and enhanced efflux activity reducing intracellular drug concentration. In biofilms, nutrient gradients and stress signals such as DNA damage induce localised persistence via the SOS response and cell-wall stress pathways. Persisters can resume growth once treatment ceases, complicating the eradication of chronic and relapsing infections. Their presence is implicated in the failure of standard therapies, fostering the emergence of true resistance through repeated exposure cycles. Understanding the molecular triggers, physiological hallmarks and environmental cues that lead to persistence is critical for designing anti-persister strategies, from efflux pump inhibitors to compounds targeting dormant cells, and for informing dosing regimens that minimise the evolution of resistance.

Research from Nature Portfolio

Consensus guidelines have recently clarified definitions and standardised assays for antibiotic persistence. By distinguishing spontaneous from triggered persistence and outlining robust single-cell and population-level measurements, these guidelines provide a framework for comparing studies and interpreting clinical relevance. This harmonisation is guiding investigations into how persistence contributes to treatment failure across diverse pathogens. In parallel, single-cell analyses of Staphylococcus aureus within host cells have revealed a stable, non-dividing persister phenotype during intracellular infection. Surviving bacteria activate stress responses—including the stringent response, cell-wall stress pathways, SOS and heat-shock networks—and maintain metabolic activity despite antibiotic challenge. This work highlights intracellular persisters as reservoirs for relapse, emphasising the need to target these cells in vivo and to consider host-cell environments when evaluating antibiotic efficacy.

Bacterial Persistence Mechanisms and Antibiotic Tolerance publication trend

The graph below shows the total number of articles in bacterial persistence mechanisms and antibiotic tolerance across all publications each year (not limited to Nature Index journals).

Technical terms

Persister cells: Phenotypic variants that survive antibiotics without genetic resistance by entering a dormant or low-metabolic state.

Antibiotic tolerance: The ability of bacteria to endure transient antibiotic exposure through non-genetic mechanisms, distinct from resistance.

Toxin–antitoxin systems: Genetic modules where a stable toxin inhibits cell growth and a labile antitoxin neutralises the toxin under non-stress conditions.

Stringent response: A global regulatory network triggered by (p)ppGpp that reallocates resources and slows growth under nutritional or environmental stress.

Efflux pumps: Membrane proteins that actively export antibiotics from the cell, lowering intracellular drug concentration and contributing to tolerance.

References

1. Bacterial persisters: molecular mechanisms and therapeutic development. Signal Transduction and Targeted Therapy (2024).
2. Definitions and guidelines for research on antibiotic persistence. Nature Reviews Microbiology (2019).
3. Antibiotic tolerance facilitates the evolution of resistance. Science (2017).
4. Intracellular Staphylococcus aureus persisters upon antibiotic exposure. Nature Communications (2020).