Nutrient Starvation Impedes Antibiotic Efficacy in Salmonella Infections

A new study from the University of Basel, published in Nature, challenges the conventional understanding of antibiotic treatment failure. Rather than being caused by a small population of highly resistant bacteria, the research points to a different explanation.

Antibiotics often prove less effective than expected in treating bacterial infections. Take Salmonella, for example, which can lead to illnesses such as typhoid fever. For years, scientists believed that a small subset of dormant bacteria—known as persisters—was the primary obstacle to successful treatment.

These persisters can survive antibiotic therapy and later trigger relapses. In response, researchers worldwide have been working to develop new strategies aimed at eliminating these so-called "sleeping" bacteria.

However, a team led by Professor Dirk Bumann at the University of Basel's Biozentrum has conducted a study that challenges this long-standing assumption.

A Shift in Perspective on Antibiotic Failure

Contrary to popular belief, antibiotic failure isn't driven by a small group of persisters. Instead, the researchers found that the majority of Salmonella bacteria in infected tissues are difficult to eradicate. Standard laboratory tests for antimicrobial clearance, they argue, create a misleading impression by suggesting only a small subset of bacteria are highly resilient.

"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."

— Dirk Bumann, Professor, University of Basel

Nutrient Starvation and Bacterial Resilience

The research team examined antimicrobial clearance in both tissue-mimicking lab models and Salmonella-infected mice. A key strategy the body employs to combat bacterial infections is reducing nutrient availability. The study found that this very process—nutrient starvation—is what makes Salmonella resistant to antibiotics. The researchers suspect this phenomenon applies to other bacterial pathogens as well.

"Under nutrient-scarce conditions, bacteria grow very slowly. This may seem beneficial at first, but it actually presents a challenge because most antibiotics only gradually kill slow-growing bacteria."

— Dirk Bumann, Professor, University of Basel

As a result, antibiotics become significantly less effective, increasing the likelihood of relapse even after prolonged treatment.

Real-Time Analysis Unveils Misconceptions

To better understand the interaction between antibiotics and bacteria, the researchers employed a novel technique that allowed them to track the real-time effects of antibiotics on individual bacterial cells.

"We demonstrated that nearly the entire Salmonella population survives antibiotic treatment for extended periods, not just a small subset of hyper-resilient persisters."

— Dr. Joseph Fanous, Study First Author, University of Basel

For decades, conventional techniques used globally have measured bacterial survival indirectly and at a slow pace, leading to distorted results.

"Traditional tests underestimate the number of surviving bacteria and falsely suggest the presence of hyper-resilient subsets of persisters that do not actually exist."

— Dr. Joseph Fanous

This misunderstanding has influenced antibiotic research for years, potentially hindering the development of more effective treatments.

New Approaches for Antibiotic Research

These findings highlight the need to rethink how antibiotic effectiveness is studied.

"Our work underlines the importance of studying bacterial behavior and antibiotic effects in real-time and under physiologically relevant conditions. In the coming years, modern methods like real-time single-cell analysis will hopefully become standard."

— Dirk Bumann

By shifting the focus from persisters to the effects of nutrient starvation, researchers may pave the way for more effective treatments for stubborn infections.

This study is part of the AntiResist initiative led by the National Center of Competence in Research (NCCR). The initiative aims to develop innovative strategies to combat bacterial infections, with Professor Dirk Bumann serving as one of its directors.

Looking Ahead

These findings call for a reassessment of antibiotic treatment strategies. Understanding the role of nutrient starvation could lead to the development of therapies that enhance antibiotic efficacy against slow-growing bacteria.

As real-time analysis techniques become more widely adopted, the future of antibiotic research may shift toward more accurate and effective approaches to combating bacterial infections.