Antibiotics have long been hailed as the miraculous defenders against bacterial infections, designed to eradicate harmful microbes with precision. However, groundbreaking research from Rutgers Health reveals a paradoxical twist in this story: certain antibiotics may inadvertently empower bacteria instead of eliminating them. This discovery not only challenges traditional views on antibiotic function but also underscores a hidden mechanism through which microbes survive and rapidly evolve drug resistance.
At the heart of this investigation lies ciprofloxacin, a widely prescribed antibiotic commonly deployed against urinary tract infections. Researchers observed that instead of merely killing the bacteria, ciprofloxacin imposes a severe bioenergetic challenge that triggers a survival mode within Escherichia coli (E. coli). This metabolic upheaval, characterized by a substantial depletion of cellular energy currency—adenosine triphosphate (ATP)—paradoxically boosts bacterial resilience and accelerates the emergence of resistant strains.
Barry Li, a doctoral candidate at Rutgers New Jersey Medical School and lead author of the study, emphasized how antibiotics are capable of altering the fundamental metabolic processes within bacterial cells. By engineering E. coli strains with genetic constructs that artificially drained ATP or nicotinamide adenine dinucleotide (NADH), molecules vital for cellular respiration and energy production, the team mimicked the energy crisis induced by ciprofloxacin. The experimental design allowed them to dissect the bacterial response to metabolic stress independent of direct antibiotic action.
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Surprisingly, the metabolic throttling did not weaken the bacteria as conventional wisdom predicted. Instead, cells countered the plunge in ATP levels by drastically ramping up their respiration rates. This hyperactive metabolic state resulted in a surge of reactive oxygen species (ROS), highly reactive molecules capable of inflicting damage on DNA. While ROS accumulation generally signals cellular harm, here it fueled two worrisome outcomes: enhanced survival of persister cells and a faster pace of mutation-driven resistance.
One of the most striking revelations was the increase in the number of persister cells—dormant stowaways that endure lethal antibiotic concentrations. Traditionally, these cells were believed to survive due to slowed metabolic activity, essentially “playing dead” to avoid drug effects. Contrary to this long-standing notion, Li and colleagues demonstrated that persisters under bioenergetic stress actually enhance their metabolism to restore energy reserves. This metabolic ramp-up triggers stress response pathways, notably the stringent response, a bacterial alarm system that reprograms cellular functions to mitigate damage and delay cell death.
The persistent survivors effectively act as a reservoir for chronic infection, lying in wait until antibiotic treatment ceases, only to resurge and reinfect. Their newfound metabolic agility calls for a paradigm shift in how scientists understand persistence and its connection to bacterial survival strategies under antibiotic pressure.
Beyond mere survival, the metabolic turmoil imposed by ciprofloxacin was found to expedite genetic mutations conferring full antibiotic resistance. By repeatedly exposing both normal and metabolically stressed E. coli to increasing doses of ciprofloxacin, the research team found stressed bacteria reached a high-level resistance threshold notably faster. Investigations into the underlying cause highlighted the dual role of oxidative DNA damage and error-prone repair mechanisms triggered by excessive reactive oxygen species. This accelerated mutation rate effectively equips bacteria with the tools to thwart not only current but potentially future antibiotic therapies.
Assistant Professor Jason Yang, senior author of the study and Chancellor Scholar in microbiology, biochemistry, and molecular genetics at Rutgers, stressed the clinical implications of these findings. He noted that the metabolic side effects of antibiotic treatment could be undermining their efficacy, as they inadvertently facilitate bacterial adaptation. This discovery challenges the conventional focus solely on direct antibiotic-bacteria interactions and points to bacterial metabolism as a critical and previously underappreciated factor in antimicrobial resistance.
The phenomenon observed is unlikely exclusive to ciprofloxacin. Initial experiments suggest that other antibiotics, such as gentamicin and ampicillin, similarly induce ATP depletion, implying a broader, perhaps universal, bioenergetic stress response across various bacterial species. This raises concerns about the treatment of infections caused by formidable pathogens like Mycobacterium tuberculosis, which have known sensitivity to metabolic fluctuations in ATP levels. Hence, the implications extend far beyond E. coli, demanding a reevaluation of how antibiotics influence bacterial physiology worldwide.
Given the scale of antibiotic resistance, which already contributes to over a million deaths annually, these insights arrive at a critical juncture. Current drug development and clinical protocols often overlook the metabolic fallout of antibiotic exposure. The Rutgers study advocates for a more nuanced approach, suggesting that screening antibiotics should include assessments of their metabolic side effects to prevent unintended enhancement of bacterial defenses.
Moreover, the researchers propose pairing conventional antibiotics with adjunct therapies designed to inhibit bacterial stress responses or to neutralize the damaging oxygen radicals produced during metabolic surges. Such “anti-evolution” boosters could blunt the bacterial adaptation machinery, preserving antibiotic potency over longer periods.
A further provocative implication challenges the entrenched medical practice of administering the highest possible antibiotic doses to overwhelm infections. Evidence from this research and prior studies indicates that extreme drug concentrations may trigger metabolic stresses that shield bacteria from death and accelerate the evolution of resistance. Thus, optimizing dosing regimens to minimize inducement of such stress responses without compromising efficacy could represent a vital paradigm shift in antibiotic stewardship.
Echoing this sentiment, Jason Yang eloquently summarized, “Bacteria turn our attack into a training camp.” The study’s exploratory next steps involve identifying compounds capable of alleviating bacterial bioenergetic stress. By interrupting this metabolic shield, scientists hope to convert the bacterial energy crisis back into an Achilles’ heel, restoring antibiotics to their designed role as microbial executioners rather than inadvertent tutors in survival.
This meticulous experimental research not only deepens our comprehension of bacterial physiology under antibiotic assault but also underscores the urgency of integrating metabolic insights into the fight against antibiotic resistance. As microbial pathogens continue to evolve swiftly, leveraging a more comprehensive understanding of their stress responses may be the key to sustaining the efficacy of the antibiotics upon which modern medicine so heavily relies.
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Subject of Research: Cells
Article Title: Bioenergetic stress potentiates antimicrobial resistance and persistence
News Publication Date: 9-Jun-2025
Web References: https://www.nature.com/articles/s41467-025-60302-6
References: DOI 10.1038/s41467-025-60302-6
Keywords: Antibiotic resistance, Drug therapy
Tags: Adenosine triphosphate depletionantibiotic resistance mechanismsantibiotic-induced resiliencebacterial survival strategiesbioenergetic challenge in bacteriaciprofloxacin effectsE. coli metabolic processesenergy crisis in bacteriaimplications for infection treatmentmicrobial evolution and drug resistancenovel antibiotic research findingsRutgers Health study
