The Role of Metabolism in Bacterial Survival and Resistance

A recent study from Rutgers Health shows that ciprofloxacin, a common treatment for urinary tract infections, triggers an energy crisis in Escherichia coli (E. coli). This stress saves many bacterial cells from being killed and speeds up the development of antibiotic resistance.

Antibiotics can actually change bacterial metabolism. We wanted to see what those changes do to the bugs’ chances of survival.

Barry Li, Study First Author, Rutgers University-New Brunswick

The study was published in Nature Communications.

Researchers Li and senior author Jason Yang focused on adenosine triphosphate (ATP), the molecule that powers cell activity. When ATP levels drop, cells experience "bioenergetic stress." To simulate this, the team engineered E. coli strains that constantly used up ATP or a related molecule, NADH. They then tested ciprofloxacin on both these modified strains and unmodified bacteria.

The results were unexpected. Both ciprofloxacin and the energy drain lowered ATP levels. But instead of slowing down, the bacteria increased their growth rate. Their respiration rose, and they produced more reactive oxygen molecules, which can damage DNA. This led to two major findings.

First, more bacterial cells survived the treatment.

In lab tests, stressed cells were ten times more likely to survive a high dose of ciprofloxacin than unstressed ones. These surviving cells, called persisters, stay inactive during treatment and can restart the infection once the drug is gone.

Previously, scientists believed that persisters formed because of slow metabolism. But Li explained, “People expected a slower metabolism to cause less killing. We saw the opposite. The cells ramp up metabolism to refill their energy tanks, which activates stress responses that slow the killing.”

Further tests linked this protection to the "stringent response," a bacterial stress reaction that alters cell behavior under pressure.

Second, stressed cells developed resistance more quickly.

While persister cells help infections linger, genetic resistance can make treatment fail completely. The researchers exposed E. coli to rising ciprofloxacin doses over time. The stressed cells reached resistance levels four cycles earlier than normal cells. DNA analysis revealed that oxidative damage and faulty DNA repair were the main causes of this resistance.

The changes in metabolism are making antibiotics work less effectively and assisting bacteria in evolving resistance.

Jason Yang, Assistant Professor and Chancellor Scholar, Microbiology, Biochemistry, and Molecular Genetics, Rutgers University-New Brunswick

Preliminary tests show that gentamicin and ampicillin, like ciprofloxacin, also reduce ATP levels. This stress response may occur in a range of infections, including Mycobacterium tuberculosis, which is especially sensitive to drops in ATP.

If confirmed, these findings could offer new insight into a global problem. Antibiotic resistance is already linked to 1.27 million deaths each year. Treatment strategies that ignore the metabolic effects of antibiotics may be overlooking a key factor.

The study suggests several ways to adjust how antibiotics are developed and used.

First, test antibiotics for their potential to drain cellular energy. Second, consider combining antibiotics with compounds that block stress responses or reduce harmful oxygen byproducts. Third, reconsider using the highest possible drug doses. Both past studies and new results suggest that high concentrations can trigger stress responses that help bacteria survive.

Yang noted, “Bacteria turn our attack into a training camp. If we can cut the power to that camp, we can keep our antibiotics working longer.”

Li and Yang now plan to study compounds that reduce bioenergetic stress. Their goal is to turn this stress from a defense mechanism into a weakness that can be targeted in treatment.