Researchers have discovered that several commonly prescribed antidepressants can promote antibiotic resistance and persistence in E. coli bacteria.
This concerning finding implicates yet another widely used class of pharmaceuticals in exacerbating the global antibiotic resistance crisis.
Key Facts:
- Antidepressants including sertraline and duloxetine were found to significantly increase E. coli’s resistance to multiple antibiotics like ciprofloxacin and chloramphenicol. Resistance emerged rapidly, within 1 day of exposure.
- In addition to resistance, antidepressants also increased the number of antibiotic-tolerant “persister” cells that can survive antibiotic treatment. Persister cells may help facilitate the evolution of resistant mutants.
- Enhanced production of reactive oxygen species (ROS) inside the bacterial cells was identified as a key mechanism driving increased antibiotic resistance following antidepressant exposure.
- Mathematical modeling predicts that over long time periods, antidepressants may accelerate the rise of antibiotic resistance and persister cell populations.
Source: PNAS (2023)
Mechanisms Behind Increased Antibiotic Resistance
The researchers systematically analyzed the impacts of five common antidepressants – sertraline, duloxetine, bupropion, escitalopram and agomelatine – on antibiotic susceptibility in E. coli.
Sertraline and duloxetine were found to be particularly potent at increasing resistance, causing over 10,000-fold increases in the ratio of antibiotic-resistant mutants to total cells following just 1 day of exposure.
Resistance was observed against multiple antibiotic classes including quinolones, tetracyclines and phenicols.
Digging deeper into the mechanisms responsible, the team found clear links between antidepressant-triggered intracellular ROS production and increased antibiotic resistance.
ROS are chemically reactive molecules containing oxygen that can damage proteins, DNA and cell membranes at high concentrations.
To keep ROS at safe levels, cells employ “scavenging” systems to eliminate excess ROS.
The researchers demonstrated that sertraline and duloxetine significantly increased ROS generation inside E. coli cells, indicating these antidepressant exposures overwhelm the cell’s ROS scavenging capacity.
Measurements showed sertraline could increase ROS levels by 90% at clinical concentrations found in the human gut.
In support of a causative role for ROS, the team found that blocking ROS production using anaerobic (oxygen-free) conditions prevented increases in antibiotic resistance following antidepressant exposure.
Furthermore, at the genetic level, sertraline and duloxetine switched on bacterial genes and pathways involved in defending against oxidative stress – like soxS and superoxide dismutase.
Overall, the results strongly suggest unchecked ROS inflicts cellular damage that drives genetic mutations conferring antibiotic resistance.
Other Contributing Factors Behind Increased Antibiotic Resistance
In addition to ROS-mediated mutagenesis, the study implicates other mechanisms by which antidepressant exposure promotes antibiotic resistance in E. coli:
Stimulation of Efflux Pumps
Efflux pumps are protein complexes in bacterial cell membranes that pump out toxic substances like antibiotics, preventing their accumulation inside cells.
The results showed sertraline and duloxetine significantly increased expression of efflux pump components, including the major AcrAB multidrug efflux pump.
Efflux pump stimulation likely acts synergistically with ROS-induced mutations to enhance antibiotic resistance.
Changes to Cell Membrane Properties
The outer membrane of gram-negative bacteria like E. coli provides an extra layer of protection, including tight regulation of porin channels that control influx of substances like antibiotics.
The researchers found antidepressant exposure altered expression of many E. coli membrane proteins and porins, including decreasing production of the OmpF porin.
This is known to restrict antibiotic entry while increasing efflux pump activity.
In total, over 200 membrane-associated genes were significantly affected by sertraline or duloxetine exposure, implicating membrane changes in enhanced antibiotic resistance.
Increased Antibiotic Persistence
In addition to stimulating “genetic” antibiotic resistance mediated by mutations, the team showed antidepressants promote increased antibiotic tolerance via formation of drug-tolerant “persister” cells.
Persister cells avoid death during antibiotic treatment through entering transient dormant states rather than outright resistance.
However, persister cells can help “buy time” for true resistant mutants to arise that can repopulate the niche after antibiotics are removed.
The study found sertraline and duloxetine increased ciprofloxacin persister cell populations in E. coli by over 50-fold at clinical concentrations. Exposure times as short as 1 day were sufficient to elevate persisters.
In support of a direct role in stimulating persistence pathways, exposure to sertraline or duloxetine increased expression of toxin-antitoxin modules and global regulators known to control persister formation.
Modeling Predicts Accelerated Antibiotic Resistance from Antidepressants
To predict long-term impacts of antidepressant exposure on bacterial evolution, the researchers developed a mathematical model tracking sensitive, persister and resistant cell populations over time.
The modeling results suggest antidepressants accelerate the rate wild-type cells evolve into antibiotic-tolerant persister and fully resistant populations.
This effect was dose-dependent, with higher antidepressant concentrations imposing stronger selective pressure for resistance.
However, the model predicts even very low, sub-clinical antidepressant concentrations can exert meaningful effects on bacterial evolutionary trajectories given sufficient time.
Antidepressants: Wider Implications for the Antibiotic Resistance Crisis
This study provides compelling evidence that a widely used class of pharmaceuticals – antidepressants – can promote antibiotic resistance and persistence in a model bacterium.
The specific mechanisms uncovered offer plausible explanations for how antidepressant exposure tips the scales in favor of resistant strains outcompeting their susceptible counterparts.
While further verification is still needed, these findings raise concerns about the wider contribution of antidepressants to the global spread of antibiotic resistance genes we face today.
Antidepressant consumption continues to grow worldwide, with the US alone using over 16,000 kg per year.
Trace levels making their way into wastewater streams may be sufficient to influence resistance gene enrichment and transfer to human pathogens.
Moving forward, much more research is required investigating antidepressant impacts across different microbial species, antibiotic compounds, dosing regimens and environmental matrices.
However, this study makes it clear that in our quest to discover all possible drivers of antibiotic resistance, we need to look well beyond conventional antibiotics.
Global Trends in Antidepressant Usage & Resistance Patterns
Increasing Antidepressant Consumption Worldwide
The global consumption of antidepressants has seen a significant rise, particularly in developed countries.
This increase is attributed to factors like better recognition of mental health conditions, wider acceptance of psychiatric medication, and broader prescribing practices.
It’s essential to examine how this trend is impacting microbial ecosystems, especially in regions with high antidepressant usage.
Geographical Variations in Antibiotic Resistance
Different regions exhibit varying levels of antibiotic resistance, often reflecting their patterns of pharmaceutical use and wastewater management.
By comparing regions with high antidepressant consumption to those with lower rates, researchers can better understand the direct and indirect impacts of these drugs on antibiotic resistance.
Impact of Healthcare Policies on Resistance Development
Countries with stringent regulations on pharmaceutical disposal and advanced wastewater treatment facilities might show different resistance patterns compared to those with less strict policies.
The role of healthcare infrastructure in controlling or exacerbating the spread of resistance is a crucial factor to consider.
Cultural and Socioeconomic Factors
The usage of antidepressants and the subsequent development of antibiotic resistance are also influenced by cultural attitudes towards mental health and medication, as well as socioeconomic factors.
For instance, in some cultures, there might be a higher reliance on medication for mental health issues, while others may lean more towards non-pharmacological approaches.
Global Health Implications
The development of antibiotic-resistant strains due to antidepressant pollution is not just a localized issue but a global health concern.
As resistant strains can spread across borders, international collaboration and policy-making are required to address this growing challenge.
The Need for Global Surveillance
There’s a growing need for international surveillance programs to monitor the impact of psychiatric medications on antibiotic resistance.
This would involve tracking prescription trends, resistance patterns, and environmental concentrations of pharmaceuticals in various parts of the world.
By understanding these global trends and their implications, health authorities, researchers, and policymakers can develop more targeted strategies to tackle the dual challenges of mental health treatment and antibiotic resistance.
References
- Study: Antibiotics can induce mutation and enhance persistence toward multiple antibiotics
- Authors: Wang et al. (2023)
