Tel Aviv [Israel], January 4: A new Israeli study is challenging one of the most entrenched assumptions in microbiology: that bacteria survive antibiotics primarily by going dormant. The research shows that antibiotic persistence is not a single biological phenomenon but instead arises from two fundamentally different growth-arrest states, a discovery that helps resolve years of contradictory findings and opens new avenues for preventing recurring infections.
Antibiotics are designed to eliminate bacteria by disrupting processes tied to growth and division. Yet in many infections, a small subset of bacterial cells survives treatment and later reignites disease. This phenomenon, known as antibiotic persistence, is a major cause of treatment failure and relapse, even when bacteria show no genetic resistance to the drugs.
For decades, persistence was largely attributed to dormancy, the idea that bacteria shut down growth in a regulated way, entering a stable, sleep-like state that shields them from antibiotics. However, new research from the Hebrew University of Jerusalem, led by PhD student Adi Rotem under the supervision of Professor Nathalie Balaban, suggests this explanation captures only part of the reality.
The study demonstrates that high survival under antibiotics can originate from two distinct physiological states, rather than simple variations of dormancy. One state fits the classic model of regulated growth arrest, in which bacteria actively slow their metabolism and maintain internal stability. The other is fundamentally different: a disrupted, dysregulated growth arrest, in which cells survive by slipping into a malfunctioning state rather than a controlled shutdown. The findings were recently published in the peer-reviewed journal Science Advances.
“We found that bacteria can survive antibiotics by following two very different paths,” Balaban said. “Once you recognize that these are distinct states, many of the contradictions in the literature suddenly make sense.”
In the regulated state, bacteria deliberately enter a protected condition. Because many antibiotics rely on active growth to be effective, these dormant cells are difficult to eliminate. This mechanism has long shaped thinking about persistence and guided experimental approaches across the field.
The disrupted state, however, challenges that paradigm. In this mode, bacteria are not calmly protecting themselves but instead exhibit a widespread loss of cellular control. Researchers found that these cells show impaired membrane homeostasis, a core function required to maintain cell integrity. Despite this dysfunction, the cells can survive antibiotic exposure and later recover, demonstrating that persistence does not require orderly dormancy.
This insight addresses a long-standing problem in persistence research. Over the years, studies have reported conflicting observations about persister cells, describing them as metabolically inactive in some experiments and highly disordered in others. According to the authors, those discrepancies likely arose because researchers were unknowingly examining different growth-arrest states while treating them as a single phenomenon.
“People were often looking for one defining signature of persistence,” the researchers noted, “but what we see is that there are at least two biologically distinct ways bacteria can get through antibiotic treatment.”
The distinction carries important practical implications. While regulated dormant cells are broadly protected, disrupted cells possess specific vulnerabilities. Their compromised membranes, the study suggests, could be exploited therapeutically, making them susceptible to treatments that would not affect classic dormant persisters.
Antibiotic persistence contributes to recurring infections ranging from chronic urinary tract infections to those associated with medical implants. By showing that persistence is not a single target but a set of distinct physiological states, the findings suggest that future therapies may need to be tailored, combining different strategies to eliminate different types of persister cells.
To uncover these differences, the research team combined mathematical modeling with high-resolution experimental techniques, including transcriptomics to track gene expression, microcalorimetry to measure metabolic activity through heat output, and microfluidic systems that allowed real-time observation of individual bacterial cells. These approaches revealed clear signatures distinguishing regulated from disrupted growth arrest.
As a result, rather than searching for a single drug capable of eliminating all lingering bacteria, scientists can now design treatments that address each survival strategy separately. Some bacteria survive by deliberately slowing down and hiding, while others persist in a damaged, unstable state. Recognizing the difference allows for more precise targeting.
Another potential application is the more strategic use of existing antibiotics. Treatment regimens could combine drugs so that one kills actively growing bacteria, another awakens dormant cells, and a third targets weakened cells with damaged membranes.
The findings also help explain why some therapies show promise in laboratory settings but fail in patients. A drug may be effective against one type of surviving bacterium while missing another. With this new understanding, researchers can test treatments in ways that more closely reflect real-world infections.
The study further opens the door to alternative approaches that do not rely solely on antibiotics. Some surviving bacteria are fragile in specific ways, particularly in their outer membranes. Therapies that exploit those weaknesses could help clear infections without contributing to antibiotic resistance. (ANI/TPS)
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