Antibiotics are indispensable for treating bacterial infections. But why are they sometimes ineffective, even when the bacteria are not resistant? In their latest study published in the journal Nature, researchers challenge the conventional view that a small subset of particularly resilient bacteria are responsible for the failure of antibiotic therapies.

In certain infectious diseases caused by bacteria, antibiotics are less effective than expected. One example is infections caused by Salmonella bacteria, which can lead to illnesses such as typhoid fever. For many years, researchers believed that a small subset of dormant bacteria was the main problem in fighting infections.

These so-called persisters can survive antibiotic treatment and cause relapses later. Researchers worldwide have been working on new therapies aimed at targeting and eliminating these "sleeping" bacteria.

In a new study,  scientists challenge 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. Scientists 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. This may seem good at first, but it 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.

The scientists used an innovative method to monitor antibiotic action in single bacteria in real time. They demonstrated that nearly the entire Salmonella population survives antibiotic treatment for extended periods, not just a small subset of hyper-resilient persisters.

Joseph Fanous et al, Limited impact of Salmonella stress and persisters on antibiotic clearance, Nature (2025). DOI: 10.1038/s41586-024-08506-6. www.nature.com/articles/s41586-024-08506-6