Bowdoin Science Journal

Sam Koegler

The Battle of the Medications: The Connection Between Antidepressants and Antibiotic Resistance in Bacteria

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         The consumption of antidepressant medications has skyrocketed in recent decades, reaching more than 337 million prescriptions written in 2016 in the United States alone (Wang et. al. 2019). For many individuals, these drugs are critical to maintaining everyday health as they treat many life-threatening psychiatric disorders. While their exact mechanisms differ, these medications travel in the bloodstream to the brain where they are able to influence the release of chemicals known as neurotransmitters that generate emotional states. However, while their intended target is the brain, these drugs continue to circulate throughout the body, thereby interacting with other organs and structures (Wang et. al. 2019).

         In their 2019 study, researchers led by Iva Lukic used data indicating the presence of antidepressants in the digestive tract to investigate the effect of these medications on the gut microbiome. After treating mice with different types of antidepressants, the team noticed a change in the types of bacteria present within the gut when compared to controls (Lukic et. al. 2019). This discovery that antidepressants could impact the types of bacteria present within the body ultimately led researcher Jianhua Guo to question the additional effects that these medications could have on bacteria. As antibiotics have also been shown to affect the composition of the gut microbiome, Guo began by investigating if the antidepressant fluoxetine could help Escherichia coli cells survive in the presence of various antibiotics. After finding that exposure to this medication did increase E. coli’s resistance to antibiotic treatments, Guo decided to expand his hypothesis to examine the overall connection of antidepressant usage with antibiotic resistance in bacteria.

        Collaborating with researchers Zue Wang and Zhigang Yue, Guo’s lab began by choosing five major types of antidepressant medications: sertraline, escitalopram, bupropion, duloxetine, and agomelatine. These medications differ in the ways that they prevent the reuptake of serotonin and norepinephrine in the brain, thereby allowing the researchers to examine the effects of various types of antidepressants that may be prescribed to patients. Then, E. coli bacteria were added to media containing varying concentrations of these five antidepressants. Once these cells were treated with antidepressants, the researchers began to test the cells’ resistance against antibiotics. In order to accurately reflect antibiotic use in the real world, the tested antibiotics covered the six main categories of antibiotic medications available on the market. The antidepressant-treated bacteria were then swabbed onto plates containing one of the tested antibiotics to observe cell growth. Based on the growth present on these plates, the researchers were able to estimate the incidence rate of bacterial resistance of E. coli bacteria treated with different antidepressants.

         Through this experiment, the lab observed that E. coli cells grown in sertraline and duloxetine, two antidepressants that inhibit the reuptake of serotonin, exhibited the greatest number of resistant cells across all the tested antibiotics (fig. 1). They also noted that E. coli cells exhibiting resistance to one antibiotic often demonstrate some level of resistance to other antibiotics as well. After detecting a correlation between antibiotic-resistance development and exposure to antidepressants, the lab tested the concentration dependence of this effect. While lowering the concentration of antidepressants seemed to decrease the amount of resistant E. coli cells, resistant cells continued to appear on the plates over time, suggesting that lowering antidepressant dosages only prolongs the process of developing antibiotic resistance.

Figure 1: These graphs showcase the change in the number of antibiotic-resistant E. coli cells after exposure to antidepressants over sixty days. The title of each graph indicates the tested antibiotic while the colored trend lines on the graph represent one of the five, tested antidepressants. On the y-axis of each graph, the fold change measurement is used to describe the change in the number of resistant cells that develop over time. As demonstrated by the purple and yellow trend lines, duloxetine and sertraline are associated with the greatest development of resistant cells to each of the four represented antibiotics. (Adapted from Wang et. al. 2019)

         After analyzing this data, the researchers were confronted with a question: what about anti-depressants led to the development of antibiotic resistance in bacteria? To examine this question, the lab used flow cytometry to examine what was happening within the bacterial cells. This lab technique uses a fluorescent dye that binds to specific intercellular target molecules, thereby allowing these components to be visualized. After applying this dye to resistant cells grown on the antibiotic agar plates, the researchers noticed the presence of specific oxygen compounds known as reactive oxygen species (ROS). Unstable ROS bind to other molecules within a cell, disrupting normal functioning and causing stress. Elevated cellular stress levels have been shown to induce the transcription of specific genes in bacteria that produce proteins to help return the cell to normal functioning (Wang et. al. 2019).

         ROS molecules have been shown to induce the production of efflux pumps in bacteria, leading the lab to investigate if these structures were involved in the antibiotic resistance of E. coli cells. Efflux pumps are structures in the cell membrane of a protein that pump harmful substances out of the cell. The lab mapped the genome to look for activated genes associated with the production of this protein. According to the computer model, more DNA regions in resistance bacteria coding for efflux pumps were active than in the Wild Type. The researchers then concluded that efflux pumps were being produced in response to antidepressant exposure. These additional efflux pumps removed antibiotic molecules in resistant E. coli, thereby allowing them to survive in the presence of lethal drugs.

         The antibiotic resistance uncovered in this study was significant and persistent. Even one day of exposure to antidepressants like sertraline and duloxetine led to the presence of resistant cells. Furthermore, the team demonstrated that these antibiotic-resistant capabilities often do not disappear over time; rather, they are inherited between generations of bacteria, leading to the proliferation of dangerous cells unsusceptible to available treatments. The next logical step towards validating the connection between antidepressants and antibiotic resistance would include studying the gut microbiomes of patients taking anti-depressants to look for antibiotic-resistant bacteria.

         This study reveals a novel issue that must be attended to.  In 2019, 1.27 million deaths worldwide could be directly attributed to antibiotic-resistant microbes, a number expected to grow to 10 million by the year 2050 (O’Neill 2023). These “superbugs” present a dangerously growing reality. If the correlation between antidepressant use and antibiotic resistance is left uninvestigated, superbugs will likely continue to develop even as antibiotic use is regulated and monitored to battle them. Only by taking this connection seriously will researchers be able to fully grapple with and battle the growing antibiotic resistance trends, thereby preventing common infections from becoming death sentences. 

 Sources:

CDC. (2022, July 15). The biggest antibiotic-resistant threats in the U.S. Centers for Disease Control and Prevention. https://www.cdc.gov/drugresistance/biggest-threats.html

Drew, L. (2023). How antidepressants help bacteria resist antibiotics. Nature. https://doi.org/10.1038/d41586-023-00186-y

Jin, M., Lu, J., Chen, Z., Nguyen, S. H., Mao, L., Li, J., Yuan, Z., & Guo, J. (2018). Antidepressant fluoxetine induces multiple antibiotics resistance in Escherichia coli via ROS-mediated mutagenesis. Environment International, 120, 421–430. https://doi.org/10.1016/j.envint.2018.07.046 

Lukić, I., Getselter, D., Ziv, O., Oron, O., Reuveni, E., Koren, O., & Elliott, E. (2019). Antidepressants affect gut microbiota and Ruminococcus flavefaciens is able to abolish their effects on depressive-like behavior. Translational Psychiatry, 9(1), 1–16. https://doi.org/10.1038/s41398-019-0466-x

O’Neill, J. (Ed.). (2016). Tackling Drug-Resistant Infections Globally: Final Report and Recommendations. The Review on Antimicrobial Resistance. https://amr-review.org/sites/default/files/160518_Final%20paper_with%20cover.pdf

Thompson, T. (2022). The staggering death toll of drug-resistant bacteria. Nature. https://doi.org/10.1038/d41586-022-00228-x

Wang, Y., Yu, Z., Ding, P., Lu, J., Mao, L., Ngiam, L., Yuan, Z., Engelstädter, J., Schembri, M. A., & Guo, J. (2023). Antidepressants can induce mutation and enhance persistence toward multiple antibiotics. Proceedings of the National Academy of Sciences, 120(5), e2208344120. https://doi.org/10.1073/pnas.2208344120

Small but Mighty: The Role of Micro-RNAs and Nanotechnology in Revolutionizing Cancer Treatment

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When you think of cancer, your mind may automatically jump to the terrifying realities of this disease: hair loss, pale skin, constant shivering, and nausea. All of these hallmarks of a cancer patient result from a current popular treatment regimen: chemotherapy. While these medications are effective for many cancer patients, they can be devastatingly hard to endure and are not always an option for every patient. Past cancer history and certain genetic mutations in tumor cells can lead to drug resistance that takes chemotherapy off the table as a treatment option. In an attempt to provide cancer patients with new medication options outside of chemotherapeutics, researchers have turned to an unassuming molecule: micro-RNA. 

Micro-RNAs (miRNAs) are short, non-coding sections of RNA that function in gene regulation cascades. Through binding to a certain region of DNA, these small biomolecules can suppress the translation of that gene into a protein. While this suppression process is a normal function of human gene regulation and protein production, dysregulation of miRNAs can lead to different levels of protein expression throughout a cell, disrupting regular maintenance processes. This dysregulation is often observed in cancer cells, as miRNAs can function as significant influencers of many hallmarks of cancer, such as cell proliferation and immortality (Ferdows, Bijan Emiliano, et al). This ability to influence cancer growth and metastasis makes miRNAs promising targets for treatments that slow the progression of tumors.

Due to the degradation of foreign RNAs in the human body, delivering miRNA treatments to target cells has proven difficult. In order to lessen this challenge, scientists have turned to nanotechnology to increase the efficacy of miRNA-targeted treatments. Nanotechnology encompasses many different organic and synthetic casings that prevent molecules from being degraded by the human body’s natural defense systems. Lipid-based nanoparticles often take the forefront of nanotechnology research. These particles are easily assimilated into the body because of their biological similarity to the lipid-based cell membrane. Cationic lipids are able to bind with the negatively charged phosphate groups in miRNA particles, creating a protective layer around these miRNA particles that can easily bind to target cells (Ferdows, Bijan Emiliano, et al). The biocompatibility found with lipid-based nanoparticles is expanded upon in extracellular vesicles, a type of molecule secreted by cells to facilitate intercellular communication. These lipid pockets are a promising target for miRNA delivery because they share many of the same biological and chemical qualities as their mother cell. Although organic nanoparticles are proving to be effective drug-delivery machines, researchers have also begun to examine the potential of using inorganic compounds to protect miRNAs from degradation. One such compound is gold-iron oxide nanoparticles (GIONS). In addition to the negatively charged GION surface that allows it to bind and transport miRNA, this nanoparticle class can also aid in the diagnosis of tumors. These particles appear on CT and MRI scans, and their appearance can help physicians determine where a tumor is located and how treatment should progress (Ferdows, Bijan Emiliano, et al).

While nanoparticle-based miRNA treatments have yet to hit mainstream cancer treatment plans, current research projects show that these medications have a promising future. In mice with transplanted lung tumors taken from human patients, cationic lipid particles have been used to deliver miRNA particles to study the effect of these treatments on patients with late-diagnosis lung cancer. Researchers used these lipid-based nanoparticles to deliver miRNA-660 to the MIR660, a gene responsible for enabling the activation of the crucial p53 tumor suppressor that results in the killing of cancer cells. In 8 weeks, the mice were shown to have 50% reduced tumor growth compared to controls, a promising result for applying this treatment in human lung cancer patients (Moro, Massimo, et al). 

GION-coated tumor-derived extracellular vesicles (TEVs) have also shown promising results as nanoparticles used in miRNA-based treatments for cancers such as breast cancer. Researchers have bound these particles to a type of naturally occurring miRNAs called anti-miRNA-21. This molecule suppresses oncomiR-21, a type of miRNA associated with assisting cancer development and growth by inhibiting apoptosis, a type of self-programmed cell death that occurs when a cell is functioning abnormally. OncomiR-21 deactivation enables a variety of proteins to regain function, allowing the cellular pathway that signals cell death to resume. When anti-miRNA-21 bound GION-TEVs were administered to breast cancer cells along with low levels of the chemotherapeutic doxorubicin, researchers found that the cells were killed almost three times quicker as compared to cells treated with doxorubicin alone (Bose RJC et al). This experimental result shows significant promise that nanoparticle-based miRNA treatments could be used in combination with chemotherapy in the future to help strengthen tumor cell apoptosis and reduce drug resistance that results from high doses of the same chemotherapeutic (Bose RJC et al). 

While these treatments show extremely significant promise, more research is needed to determine their efficacy in human patients. Specifically, inorganic nanoparticles such as GIONs require additional research to ensure their delivery is minimally toxic to human patients (Ferdows, Bijan Emiliano, et al). Fortunately, the results of current experiments demonstrate that nanoparticle-based miRNA cancer drugs could have a significant role in the future treatment of cancer patients. These treatments are minimally invasive and have the potential to allow physicians and researchers to target miRNAs to patient-specific genetic markers in tumor cells. This individualization could give patients with uniquely mutated tumors a chance for a longer lifespan or remission. In addition, the use of these treatments could reduce reliance on chemotherapy, thereby lessening drug resistance found in cancer patients with tumor recurrences (Ferdows, Bijan Emiliano, et al). Through further funding and research, nanoparticle-based miRNA cancer treatments could become the next big wave of cancer drugs to hit hospitals across the world, giving patients new hope for recovery and life after cancer. 

 

References

Bose RJC, Uday Kumar S, Zeng Y, Afjei R, Robinson E, Lau K, Bermudez A, Habte F, Pitteri SJ, Sinclair R, Willmann JK, Massoud TF, Gambhir SS, Paulmurugan R. Tumor Cell-Derived Extracellular Vesicle-Coated Nanocarriers: An Efficient Theranostic Platform for the Cancer-Specific Delivery of Anti-miR-21 and Imaging Agents. ACS Nano. 2018 Nov 27;12(11):10817-10832. doi: 10.1021/acsnano.8b02587. Epub 2018 Oct 22. PMID: 30346694; PMCID: PMC6684278.

Ferdows, Bijan Emiliano, et al. “RNA Cancer Nanomedicine: Nanotechnology-Mediated RNA Therapy.” Nanoscale, vol. 14, no. 12, 2022, pp. 4448–55. DOI.org (Crossref), https://doi.org/10.1039/D1NR06991H.

Moro, Massimo, et al. “Coated Cationic Lipid-Nanoparticles Entrapping MiR-660 Inhibit Tumor Growth in Patient-Derived Xenografts Lung Cancer Models.” Journal of Controlled Release, vol. 308, Aug. 2019, pp. 44–56. DOI.org (Crossref), https://doi.org/10.1016/j.jconrel.2019.07.006.