Study reveals bacterial strategy behind antibiotic tolerance and persistence

Antibiotics are a medical marvel, but many microbes are gaining the ability to resist and tolerate these therapeutics. St. Jude Children's Research Hospital scientists have uncovered how S. pneumoniae adapts to antibiotic exposure and immune pressures. Their findings reveal that changes in RNA regulation enable bacteria to enter a state of antibiotic tolerance. The results provide a deeper understanding of how pathogens survive treatment and could inform strategies to improve the effectiveness of existing antibiotics. The findings were published today in Cell Host & Microbe.

For children with cancer and other conditions that weaken the immune system, bacterial infections remain a significant clinical challenge because immune suppression can make infections more difficult to control and increase the risk of serious complications. S. pneumoniae, a leading cause of serious bacterial infections worldwide, can be particularly dangerous in these patients and may cause severe illnesses, including pneumonia, bloodstream infections and meningitis. While antibiotics are critical for preventing and treating these infections, some bacteria can survive antibiotic exposure through mechanisms such as antibiotic resistance or antibiotic tolerance.

Being able to target the bacterial populations that are refractory to antibiotic treatment is absolutely critical. We have uncovered a new strategy for how bacteria respond to antibiotics, which provides new insights into how persistent infections develop. These insights could guide the strategies to improve antibiotic effectiveness."

Jason Rosch, PhD, corresponding author, St. Jude Department of Host-Microbe Interactions

Host pressures drive bacterial survival strategies beyond resistance

Using an infection model that tracked how S. pneumoniae evolved within the host, the researchers found that the pressures of the host environment and immune system shaped S. pneumoniae evolution. This evolution favored adaptations that allowed the bacteria to tolerate antibiotic exposure while maintaining their ability to persist rather than acquire resistance mutations that could compromise their fitness during infection.

Single-cell analyses revealed that this tolerance strategy involved a bet-hedging response, in which the bacterial population adopted different survival states in response to antibiotic stress. While many bacterial cells headed toward cell death after antibiotic exposure, a subset entered a temporary state of antibiotic tolerance, slowing normal cellular activity and reducing the damage caused by treatment.

The researchers found that this response was driven by changes in RNA regulation, including mutations in rny, a gene involved in RNA degradation. Tolerant cells prevented the cellular damage typically caused by antibiotics and entered a protective low-activity state that allowed them to survive treatment and rapidly resume growth once antibiotics were removed.

"It's essentially a population-based survival strategy," said Rosch. "If every cell responded to antibiotics in the same way, the population would be less likely to survive. Instead, we found that while most cells died, a small subset transiently survived antibiotic exposure and drove regrowth after treatment ended."

These findings highlight the importance of understanding how bacteria survive antibiotic exposure. This knowledge is critical for designing novel antibiotics and enhancing their performance.

"I think this really opens our eyes to the fact that bacteria have many more strategies for evading antibiotics than we currently appreciate," said Rosch. "Antibiotic treatment can fail even in the absence of traditional resistance. This reveals the importance of tolerance mechanisms that allow bacteria to persist, which willhelp guide new strategies to improve antibiotic effectiveness."