Fueling the Fight: How Bacterial Metabolism Drives Antibiotic Resistance and Persistence
- Ray Sullivan
- Jun 26
- 3 min read
The global rise of antimicrobial resistance (AMR) is a daunting challenge for modern medicine, directly contributing to over a million deaths in 2019 alone. Understanding the complex ways bacteria evade antibiotics is crucial, and new research sheds light on a surprising culprit: "bioenergetic stress".
Imagine a cell constantly struggling to balance its energy budget. That's bioenergetic stress. It occurs when a cell's consumption of ATP (adenosine triphosphate), the primary energy currency, outstrips its production, leading to a decrease in the crucial ATP/ADP ratio and adenylate energy charge. This state can be induced by various conditions, including antibiotic treatment itself.
Our Society's Vice President, Jason Yang at Rutgers New Jersey Medical School led a team of researchers who used a clever synthetic biology approach in Escherichia coli to directly study bioenergetic stress. By engineering bacteria to continuously hydrolyze ATP or oxidize NADH, they created conditions where ATP or NADH consumption increased, effectively inducing bioenergetic stress. These engineered cells showed expected signs of stress, including decreased ATP/ADP and NADH/NAD+ ratios, extended lag phases, and enhanced respiration and glycolysis.
One of the most striking findings was that bioenergetic stress significantly accelerates the evolution of antibiotic resistance. While the initial minimum inhibitory concentration for ciprofloxacin wasn't altered by bioenergetic stress, serial passage experiments showed a statistically significant enhancement in resistance evolution in the stressed bacterial populations.
This acceleration isn't due to changes in basal mutation rates. Instead, it stems from stress-induced mutagenesis. The study revealed that bioenergetic stress dramatically increases the production of reactive oxygen species (ROS), such as hydrogen peroxide. This increased ROS accumulation leads to oxidative damage to cellular components, including DNA, specifically creating highly mutagenic 8-oxo-deoxyguanosine.
The enhanced ROS production, driven by increased cellular respiration, then triggers specific DNA repair mechanisms that introduce mutations. The study implicated two key pathways:
Mutagenic Break Repair: Bioenergetic stress potentiates the formation of hyper-mutagenic "gambler cells". This process involves the stringent response and low-fidelity DNA polymerases that introduce mutations during DNA repair.
Transcription-Coupled Repair: Oxidative DNA lesions induce stalled RNA polymerases, which recruit the DNA translocase, Mfd protein, to initiate mutagenic nucleotide excision repair.
Beyond resistance, bioenergetic stress also potentiates antibiotic persistence. Persister cells are a subpopulation of bacteria that exhibit prolonged survival under bactericidal stress without being genetically resistant.
Surprisingly, while bioenergetic stress induced enhanced respiration and ROS production, which were previously associated with increased antibiotic lethality, these highly metabolically active cells actually showed enhanced persistence when bioenergetically stressed. This challenges the common notion that persistence requires metabolic dormancy.
The mechanism for this enhanced persistence was identified as the stringent response. This general stress response, mediated by a signaling molecule produced by bacteria in response to stress, the alarmone, induces growth inhibition and metabolic dormancy, allowing bacteria to survive stressful conditions. Experiments showed that disrupting the stringent response abolished the bioenergetic stress-enhanced persistence.
Crucially, the researchers demonstrated that bioenergetic stress itself, rather than just high respiration or ROS, is a stronger determinant of persistence. By rapidly switching bacterial cells between rich and minimal media, they could induce or alleviate bioenergetic stress and directly observe its impact on persistence.
The findings propose a new model where antibiotic lethality and persistence are determined by the balance between ATP consumption and production, not just the absolute concentration of intracellular ATP.
This model suggests that:
High, balanced ATP consumption and production (e.g., during exponential growth) lead to higher antibiotic lethality.
If ATP consumption rapidly increases before production can catch up, or if production decreases, bioenergetic stress increases, and antibiotic lethality decreases (leading to persistence via the stringent response).
This new understanding even provides a potential explanation for the "Eagle effect," where very high antibiotic concentrations can paradoxically decrease lethality.
These insights have significant implications. They enrich our understanding of why antibiotic cross-resistance is widespread and suggest that the host environment, which can induce bioenergetic stress (like hypoxia or oxidative stress), might play a key role in driving AMR and persistence, particularly in diseases like tuberculosis.
Further research into the molecular mechanisms linking bioenergetic stress to increased mutation rates will be vital. This knowledge could lead to the development of "anti-evolution drug adjuvants" – therapies designed not to kill bacteria, but to curb the evolution of resistance, offering a new weapon in our ongoing fight against superbugs.
This work highlights the critical interplay between bacterial metabolism, stress responses, and antibiotic efficacy, paving the way for novel strategies to combat the global AMR crisis.
Li B, Srivastava S, Shaikh M, Mereddy G, Garcia MR, Chiles EN, Shah A, Ofori-Anyinam B, Chu TY, Cheney NJ, McCloskey D, Su X, Yang JH. Bioenergetic stress potentiates antimicrobial resistance and persistence. Nat Commun. 2025 Jun 9;16(1):5111. doi: 10.1038/s41467-025-60302-6. PMID: 40490453; PMCID: PMC12149317.
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