Antibiotics May Help Bacteria Accelerate Treatment Resistance

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Antibiotics May Help Bacteria Accelerate Treatment Resistance


Antibiotics May Help Bacteria Accelerate Treatment Resistance
Credit: Artur Plawgo/Getty Images

While antibiotics are designed to kill bacteria, new research now shows they can also provide bacteria with an unexpected advantage. In a study published in Nature Communications, researchers at Rutgers Health show that ciprofloxacin, an antibiotic commonly used to treat urinary tract infections, induces a metabolic state in Escherichia coli (E. coli) that increases both survival and speeds the evolution of antibiotic resistance.

“Antibiotics can actually change bacterial metabolism,” said first author Barry Li, an MD/PhD student at Rutgers New Jersey Medical School. “We wanted to see what those changes do to the bugs’ chances of survival.”

The research team, led by Li and senior author Jason Yang, PhD, focused their study on adenosine triphosphate (ATP), the main energy source in cells, and how its depletion under antibiotic treatment affects bacterial survival. To do this, they engineered E. coli strains with genetic constructs that constantly consumed ATP or NADH, to induce a condition known as “bioenergetic stress.” The researchers then exposed these strains and normal bacteria to ciprofloxacin.

Counter to current thinking, the dramatically lower levels of ATP and resulting stress on the bacteria did not thwart them, and instead revved up their activity. “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.”

This finding is contrary to longstanding beliefs that metabolic dormancy and slow growth promote bacterial persistence. In time-kill experiments, the ATP-stressed E. coli strains were ten times more likely to survive ciprofloxacin exposure than unstressed strains, suggesting that bioenergetic stress enhances the formation of persister cells. These persister cells survive treatment and can later repopulate, reigniting infection.

“Bioenergetic stress potentiates antibiotic persistence via the stringent response,” the researchers wrote. The bacterial stress response Li and Yang found reprograms cells to endure harsh conditions, including antibiotic exposure.

The study also revealed that stressed bacteria evolved genetic resistance more rapidly. When the team subjected E. coli to gradually increasing ciprofloxacin doses, the ATP-stressed strains reached high-level resistance in four fewer cycles than normal strains. Genomic sequencing showed that increased reactive oxygen species (ROS), which are byproducts of heightened respiration caused by bioenergetic stress, were damaging DNA and triggering often faulty repair mechanisms.

“Bioenergetic stress accelerates fluoroquinolone resistance evolution via a stress-induced mutagenesis mechanism involving ROS, mutagenic break repair, and transcription-coupled repair,” the researchers wrote. Importantly, they observed that this form of stress-enhanced mutagenesis did not increase baseline mutation rates, it occurred only when the bacteria were influenced by the antibiotic.

In prior work, the investigators had shown that fluoroquinolone antibiotics such as ciprofloxacin could disrupt ATP levels. The new study adds to that finding by defining bioenergetic stress more precisely and demonstrated this stress manifests in a bacterial infection.

The team also tested the antibiotics gentamicin and ampicillin against their engineered E. coli strains and observed similar ATP depletion, which suggests that energy-draining effects likely extend across drug classes and bacterial species, including Mycobacterium tuberculosis, which is known to be highly sensitive to ATP disruption.

A model Li and Yang developed based on this finding indicates that antibiotic efficacy is not simply a matter of drug concentration, but of the metabolic balance between ATP consumption and production.

“Our model predicts a zone of antibiotic efficacy for bactericidal antibiotics: at moderate antibiotic treatment concentrations, enhanced ATP consumption induces compensatory hypermetabolic ATP production that enhances lethality…while at very high antibiotic concentrations…lethality is decreased as a consequence of the increased bioenergetic stress,” they wrote

The research has several potential clinical and therapeutic implications including:

  • Screening new antibiotics for unintended ATP-draining effects;
  • Combining current antibiotics with “anti-evolution” adjuvants that buffer ROS or block stress responses could prevent resistance; and
  • Reconsideration of prescribing maximum tolerated doses, as extreme concentrations may paradoxically promote survival and resistance.

The researchers noted some limitations of their study, specifically that the experiments were performed in laboratory strains of E. coli, and the generalizability of the findings to clinical isolates or other pathogens like Salmonella or M. tuberculosis will still need to be tested.

Future research will focus on identifying compounds that mitigate bioenergetic stress and testing whether similar effects occur in more clinically relevant settings, such as biofilms or host immune environments.



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