Tel Aviv [Israel], January 4 (ANI/TPS): 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 paths 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. But new research at the Hebrew University of Jerusalem, led by PhD student Adi Rotem under the supervision of Prof. Nathalie Balaban, shows that this explanation captures only part of the reality.
The study demonstrates that high survival under antibiotics can originate from two distinct physiological states, not merely 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 Science Advances journal.
“We found that bacteria can survive antibiotics by following two very different paths,” said Balaban. “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 kill. This mechanism has long dominated thinking about persistence and has shaped 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. The 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 studying different growth-arrest states and 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 has practical implications. While regulated dormant cells are broadly protected, disrupted cells carry 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 plays a role in recurring infections ranging from chronic urinary tract infections to infections 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 persister types.
To uncover these differences, the team combined mathematical modeling with high-resolution experimental approaches, 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 methods revealed clear signatures separating regulated and disrupted growth arrest.
As a result of the study, instead of trying to invent one “magic” drug that kills all lingering bacteria, scientists can now design treatments that deal with each survival strategy separately. Some bacteria survive by deliberately slowing down and hiding, while others survive in a damaged, unstable state. Knowing the difference makes it possible to target them more precisely.
Another application is the smarter use of existing antibiotics. Treatments could be combined so that one drug kills actively growing bacteria, another wakes up dormant ones, and a third attacks weakened cells with damaged membranes.
The findings also help explain why some drugs look promising in the lab but fail in real patients. A treatment may work well against one type of surviving bacteria but miss the other. With this new understanding, researchers can test drugs more realistically.
The study also opens the door to new kinds of treatments that do not rely solely on antibiotics. Some of the surviving bacteria are fragile in specific ways, especially in their outer membranes. Therapies that take advantage of those weaknesses could help clear infections without adding to antibiotic resistance. (ANI/TPS)