New study reveals bacteria can survive antibiotic treatment through two fundamentally different “shutdown modes,” not just the classic idea of dormancy. The researchers show that some cells enter a regulated, protective growth arrest, a controlled dormant state that protects them from antibiotics, while others survive in a disrupted, dysregulated growth arrest, a dysfunctional state characterized by vulnerabilities, particularly reduced cell membrane stability. This distinction is important because antibiotic persistence is a major cause of treatment failure and recurrent infections even when the bacteria are not genetically resistant, and has remained scientifically puzzling for years, with studies reporting conflicting results. By demonstrating that persistence can arise from two different biological states, the work helps explain these contradictions and provides a practical way forward: different types of persistence may require different treatment strategies, making it possible to design more effective treatments that prevent the recurrence of infections.
Antibiotics are supposed to kill harmful bacteria. However, in many persistent infections, a small number of bacterial cells manage to survive, only to reappear later and cause a relapse. This phenomenon, known as antibiotic persistence, is a major driver of treatment failure and one reason why infections can be so difficult to treat completely.
For years, persistence has been largely blamed on the bacteria shutting down and lying dormant, essentially a kind of sleep that protects them from antibiotics designed to target active growth. But new research led by PhD student Adi Rotem under the guidance of Professor Nathalie Balaban from the Hebrew University reveals that this explanation only tells part of the story.
The study shows that high survival with antibiotics may come from two fundamentally different states of growth arrest and are not just variants of the same “sleep” behavior. One is a controlled, adjustable shutdown, the classic idle model. The other is something completely different: a disrupted, dysregulated standoff, where bacteria survive not by protective quiescence but by entering a dysfunctional state with distinct vulnerabilities.
“We found that bacteria can survive antibiotics by following two very different pathways,” said Professor Balaban. “Recognizing the difference helps resolve years of conflicting results and indicates more effective treatment strategies.”
Two “ways of survival” and why they matter
Researchers have identified two growth arrest archetypes that can both lead to persistence, but for very different reasons:
1) Adjustable growth arrest: Protected idle state
In this mode, the bacteria deliberately slow down and enter a stable, protected state. These cells are harder to kill because many antibiotics rely on bacterial growth to be effective.
2) Arrested Development: Survival Through Breakdown
In the second mode, the bacteria enter a deregulated and disordered state. This is not a programmed shutdown, but a loss of normal cellular control. These bacteria exhibit widespread impairment of membrane homeostasis, a key function required to maintain cell integrity.
This weakness could become a key treatment target.
A framework that could transform antibiotic strategies
Antibiotic persistence plays a role in recurrent infections in a wide range of settings, from chronic urinary tract infections to infections associated with medical implants. However, despite intense research, scientists have struggled to agree on a single mechanism that explains why persistent cells survive. Different experiments have produced conflicting results about what perseverants look like and behave.
This study offers one explanation: the researchers may have been observing different types of bacteria that stopped growing without recognizing that they were distinct.
By separating persistence into two distinct physiological states, the findings suggest a future where treatments could be tailored, targeting dormant persisters in one way and disturbed persisters in another.
How researchers saw what others were missing
The team combined mathematical modeling with several high-resolution experimental tools, including:
- Transcriptomicsto measure how bacterial gene expression changes under stress
- Microcalorimetryto monitor metabolic changes via microscopic heat signals
- Microfluidsallowing scientists to observe individual bacterial cells under controlled conditions
Together, these approaches have revealed distinct biological signatures that distinguish regulated growth arrest from growth arrest arrest, along with the specific vulnerabilities of the disrupted state.
