Antibiotic resistance linked to lack of nutrients, not tough bacteria

A new study from the University of Basel has challenged the long-held belief that ‘persister’ bacteria are the primary reason for antibiotic treatment failures. Researchers have discovered that nutrient starvation is the main culprit behind the reduced effectiveness of antibiotics in certain infections. The findings, published in the journal Nature, could revolutionise antibiotic research and lead to the development of more effective therapies.

For years, scientists have believed that infections like typhoid fever, caused by Salmonella bacteria, persist because of a small population of dormant bacteria known as persisters. These persisters are thought to survive antibiotic treatment and subsequently cause relapses. This theory has driven research into therapies specifically targeting these supposedly resilient bacteria.

However, Professor Dirk Bumann’s team at the Biozentrum of the University of Basel has now debunked this prevailing concept. “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. He added, “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 scarcity: the real reason for antibiotic failure

The research team investigated antimicrobial clearance in Salmonella-infected mice and tissue-mimicking laboratory models. They discovered that the body’s natural defences against bacteria, which often involve reducing nutrient availability, are the key factor in Salmonella survival. The researchers believe this mechanism likely applies to other bacterial pathogens as well.

“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.” Consequently, the antibiotics become significantly less effective, leading to potential relapses even after extended treatment.

Real-time analysis reveals misconception

The scientists employed an innovative method to monitor the effects of antibiotics on individual 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 critical flaw in standard testing methods, used globally for decades, lies in their indirect and delayed measurement of bacterial survival, which leads to skewed 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 significantly influenced the direction of research for many years.

A new direction for antibiotic research

These findings have the potential to fundamentally reshape antibiotic research. “Our work underlines the importance of studying bacterial behaviour and antibiotic effects live and under physiologically relevant conditions,” says Bumann. “In a few years, modern methods like real-time single-cell analysis will hopefully become standard.” The shift in focus from persisters to the impact of nutrient starvation represents a crucial step towards developing more effective therapies for challenging infections.

This research is part of the National Center of Competence in Research (NCCR) ‘AntiResist’, a research consortium dedicated to developing innovative strategies to combat bacterial infections. 

This study was published in Nature.