A new study from Rutgers Health reveals that ciprofloxacin, a standard treatment for urinary tract infections, triggers an energy crisis in Escherichia coli (E. coli) that saves many cells from death and accelerates the evolution of antibiotic resistance.
“Antibiotics can actually change bacterial metabolism,” said Barry Li, a student at Rutgers New Jersey Medical School and first author of the paper. “We wanted to see what those changes do to the bugs’ chances of survival.”
Li and senior author Jason Yang focused on adenosine triphosphate (ATP), the molecular fuel that powers cells. When ATP levels crash, cells experience “bioenergetic stress.”
Why was the bacteria’s survival surprising?
To mimic bioenergetic stress, the team engineered E. coli with genetic drains that constantly burned ATP or its cousin nicotinamide adenine dinucleotide (NADH). Then, they pitted both the engineered strains and normal bacteria against ciprofloxacin.
The results surprised the researchers. The drug and the genetic drain each slashed ATP, but rather than slowing down, the bacteria revved up. Respiration soared, and the cells spewed extra reactive‑oxygen molecules that can damage DNA.
This produced two troubling outcomes. First, more of the bacterial cells survived.
In time‑kill tests, ten times as many stressed cells survived a lethal ciprofloxacin dose compared with unstressed controls. These hardy stragglers, known as persister cells, remain dormant until the drug is eliminated, and then they rebound to initiate a new infection.
People have long blamed sluggish metabolism for persistent cell formation, Li explained.
“People expected a slower metabolism to cause less killing,” Li said. “We saw the opposite. The cells ramp up metabolism to refill their energy tanks, and that turns on stress responses that slow the killing.”
Follow-up experiments traced the protection to the stringent response, a bacterial alarm system that preprogrammes the cell in response to stress.
Secondly, stressed cells mutated faster to evolve antibiotic resistance.
Genetic cell changes fuel antibiotic resistance
While persisters keep infections smouldering, genetic antibiotic resistance can render a drug useless outright. The Rutgers group cycled E. coli through escalating ciprofloxacin doses and found that stressed cells reached the resistance threshold four rounds sooner than normal cells. DNA sequencing and classic mutation tests indicated that oxidative damage and error-prone repair were the culprits.
“The changes in metabolism are making antibiotics work less well and helping bacteria evolve resistance,” explained Yang, an assistant professor at the medical school and Chancellor Scholar of microbiology, biochemistry & molecular genetics.
Preliminary measurements show that gentamicin and ampicillin also drain ATP in addition to ciprofloxacin. The stress effect may span a wide range of pathogens, including Mycobacterium tuberculosis, which is highly sensitive to ATP shocks.
Casting new light on a huge global health threat
Antibiotic resistance already contributes to 1.27 million deaths a year. Strategies that overlook the metabolic consequences of treatment may be missing a crucial lever.
The findings suggest several changes for the development and use of antibiotics.
Firstly, screen candidate antibiotics for unintended energy‑drain side effects. Second, pair existing drugs with anti‑evolution boosters that block the stress pathways or mop up the extra oxygen radicals. Third, reconsider the instinct to blast infections with the highest possible dose. Earlier studies and the new data both hint that extreme concentrations can trigger the very stress that protects bacteria.
“Bacteria turn our attack into a training camp,” Yang concluded. “If we can cut the power to that camp, we can keep our antibiotics working longer.”
Li and Yang are planning to test compounds that soothe bioenergetic stress, hoping to turn the microbial energy crisis back into an Achilles’ heel rather than a shield.
