Antibiotic failure is mainly due to nutrient-starved bacteria, not persisters, making infections harder to treat. Real-time analysis suggests a shift in antibiotic research focus.
Antibiotics are essential for treating bacterial infections, yet they sometimes fail even when bacteria are not resistant. A recent study published in Nature by researchers at the University of Basel challenges the long-held belief that antibiotic treatment failures are primarily due to a small group of highly resilient bacteria.
In certain bacterial infections, antibiotics do not work as effectively as expected. A notable example is infections caused by Salmonella, which can lead to illnesses such as typhoid fever. For years, scientists have believed that a subset of dormant bacteria—known as persisters—are the primary obstacle to successful treatment. These bacteria can survive antibiotic exposure and later trigger relapses. In response, researchers worldwide have been developing new therapies to specifically target and eliminate these dormant bacteria.
In a new study, Professor Dirk Bumann’s team from the Biozentrum of the University of Basel challenges the prevailing concept that persisters are the cause of antibiotic ineffectiveness. “Contrary to widespread belief, antibiotic failure is not caused by a small subset of persisters. In fact, the majority of Salmonella in infected tissues are difficult to kill,” explains Bumann. “We have been able to demonstrate that standard laboratory tests of antimicrobial clearance produce misleading results, giving a false impression of a small group of particularly resilient persisters.”
Nutrient starvation increases Salmonella resilience
The researchers investigated antimicrobial clearance in both Salmonella-infected mice and tissue-mimicking laboratory models. The body’s defense mechanisms against bacteria often include reducing the availability of nutrients. The researchers have now revealed that in fact, this nutrient starvation is the main reason for Salmonella bacteria surviving treatments with antibiotics. The researchers assume that the same applies to other bacterial pathogens.
“Under nutrient-scarce conditions, bacteria grow very slowly,” says Bumann. “This may seem good at first, but is actually a problem because most antibiotics only gradually kill slowly growing bacteria.” As a result, the drugs are much less effective, and relapses can occur even after prolonged therapy.
Real-time analyses reveal misconception
The scientists used an innovative method to monitor antibiotic action in single bacteria in real-time. “We demonstrated that nearly the entire Salmonella population survives antibiotic treatment for extended periods, not just a small subset of hyper-resilient persisters,” says Dr. Joseph Fanous, the study’s first author.
A major issue with the standard methods used worldwide for decades is their indirect and delayed measurement of bacterial survival, leading to distorted results. “Traditional tests underestimate the number of surviving bacteria,” explains Fanous. “And they falsely suggest the presence of hyper-resilient subsets of persisters that do not actually exist.” This misinterpretation has influenced research for many years.
Novel tools for antibiotics research
These findings could fundamentally change antibiotic research. “Our work underlines the importance of studying bacterial behavior and antibiotic effects live and under physiologically relevant conditions,” emphasizes Bumann. “In a few years, modern methods like real-time single-cell analysis will hopefully become standard.” Shifting the focus from persisters to the impact of nutrient starvation is an important step toward more effective therapies against difficult-to-treat infections.
Website: International Conference on Infectious Diseases
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