Antimicrobial Synergy Between Antidepressants and Antibiotics: Mechanisms and Safety Implications

Document Type : Review article

Authors

1 Student research committee, Arak University of Medical Sciences, Arak, Iran

2 Infectious Diseases Research Center (IDRC), Arak University of Medical Sciences, Arak, Iran

10.22038/mjms.2025.88620.5035

Abstract

Resistance to antimicrobial agents poses a significant threat to global public health, necessitating urgent development of novel therapeutic strategies to combat drug-resistant pathogens. Antidepressants, which have been traditionally used to treat depressive disorders, have recently attracted considerable attention in the field of non-antibiotic drug research due to their multiple pharmacological properties, including antimicrobial, anticancer, and anti-inflammatory activities. In addition to their direct antimicrobial activities, recent studies have shown that these drugs can act as adjuvants to enhance the efficacy of conventional antibiotics against resistant bacteria. This synergistic effect has been demonstrated, especially in combination with antibiotics such as quinolones, aminoglycosides, carbapenems, tetracyclines, polymyxin B and sulfonamides, against bacteria such as Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, Helicobacter pylori, Staphylococcus aureus and Enterococcus spp. The mechanisms of these effects appear to be related to inhibition of bacterial efflux pumps, suppression of microbial growth and proliferation, anti-biofilm activity and compromise of cell membrane integrity. Nonetheless, the utilization of antidepressants represents potential risks. These compounds may disturb the intestinal microbiota, leading to dysbiosis and possibly contributing to the development of antibiotic resistance. Also, their persistence in the environment and entry into the food chain has raised concerns about human health and the ecosystem. This review discusses both the antibacterial synergistic effects and underlying mechanisms of tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) in combination with antibiotics, as well as the associated safety and environmental considerations.

Keywords

References

  1. Farha MA, Brown ED. Drug repurposing for antimicrobial discovery. Nature microbiology. 2019;4(4):565-77.
  2. Magill SS, Edwards JR, Bamberg W, Beldavs ZG, Dumyati G, Kainer MA, et al. Multistate point-prevalence survey of health care-associated infections. The New England journal of medicine. 2014;370(13):1198-208.
  3. Shariati A, Kashi M, Chegini Z, Hosseini SM. Antibiotics-free compounds for managing carbapenem-resistant bacteria; a narrative review. Frontiers in pharmacology. 2024;15:1467086.
  4. Organization WH. Global antimicrobial resistance and use surveillance system (GLASS) report 2022: World Health Organization; 2022.
  5. Gill EE, Franco OL, Hancock RE. Antibiotic adjuvants: diverse strategies for controlling drug‐resistant pathogens. Chemical biology & drug design. 2015;85(1):56-78.
  6. Khoshbayan A, Narimisa N, Elahi Z, Bostanghadiri N, Razavi S, Shariati A. Global prevalence of mutation in the mgrB gene among clinical isolates of colistin-resistant Klebsiella pneumoniae: a systematic review and meta-analysis. Frontiers in microbiology. 2024;15:1386478.
  7. Gajdács M, Spengler G. The role of drug repurposing in the development of novel antimicrobial drugs: Non-antibiotic pharmacological agents as quorum sensing-inhibitors. Antibiotics. 2019;8(4):270.
  8. Tyers M, Wright GD. Drug combinations: a strategy to extend the life of antibiotics in the 21st century. Nature Reviews Microbiology. 2019;17(3):141-55.
  9. Yi H, Yuan G, Li S, Xu X, Guan Y, Zhang L, et al. Drug Combinations to prevent antimicrobial resistance: various correlations and laws, and their verifications, thus proposing some principles and a preliminary scheme. Antibiotics. 2022;11(10):1279.
  10. Caldara M, Marmiroli N. Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications. Pharmaceuticals. 2021;14(9):915.
  11. Gonzalez-Bello C, Rodríguez D, Pernas M, Rodriguez A, Colchon E. β-Lactamase inhibitors to restore the efficacy of antibiotics against superbugs. Journal of medicinal chemistry. 2019;63(5):1859-81.
  12. González-Bello C. Antibiotic adjuvants–A strategy to unlock bacterial resistance to antibiotics. Bioorganic & medicinal chemistry letters. 2017;27(18):4221-8.
  13. Xiao G, Li J, Sun Z. The combination of antibiotic and non-antibiotic compounds improves antibiotic efficacy against multidrug-resistant bacteria. International Journal of Molecular Sciences. 2023;24(20):15493.
  14. Harmer CJ, Duman RS, Cowen PJ. How do antidepressants work? New perspectives for refining future treatment approaches. Lancet Psychiatry. 2017;4(5):409-18.
  15. Butts A, Reitler P, Nishimoto AT, DeJarnette C, Estredge LR, Peters TL, et al. A Systematic Screen Reveals a Diverse Collection of Medications That Induce Antifungal Resistance in Candida Species. Antimicrob Agents Chemother. 2019;63(5).
  16. Ellezian L, Jhawar A, Kyono Y, Flowers SA. Psychotropic Drugs in the Discussion of Antimicrobial-Resistant Microorganisms. DNA Cell Biol. 2022;41(11):919-23.
  17. Golden SR, Rosenstein DL, Belhorn T, Blatt J. Repurposing Psychotropic Agents for Viral Disorders: Beyond Covid. Assay Drug Dev Technol. 2021;19(6):373-85.
  18. Rácz B, Spengler G. Repurposing Antidepressants and Phenothiazine Antipsychotics as Efflux Pump Inhibitors in Cancer and Infectious Diseases. Antibiotics (Basel, Switzerland). 2023;12(1).
  19. Ding L, Chen X, Lv Y, Peng Q, Wang R, Yang B, et al. Research progress on the synergistic effect and its mechanisms of antidepressants and antibiotics against resistant pathogens. Archives of microbiology. 2025;207(7):157.
  20. Glajzner P, Bernat A, Jasińska-Stroschein M. Improving the treatment of bacterial infections caused by multidrug-resistant bacteria through drug repositioning. Frontiers in Pharmacology. 2024;15:1397602.
  21. Jimenez XF. Beyond depression: Other uses for tricyclic antidepressants. Cleveland Clinic Journal of Medicine. 2019;86(12):807.
  22. Bonilla-Jaime H, Sánchez-Salcedo JA, Estevez-Cabrera MM, Molina-Jiménez T, Cortes-Altamirano JL, Alfaro-Rodríguez A. Depression and pain: use of antidepressants. Current 2022;20(2):384-402.
  23. Dell'Osso L, Carmassi C, Mucci F, Marazziti D. Depression, Serotonin and Tryptophan. Current pharmaceutical design. 2016;22(8):949-54.
  24. Lochmann D, Richardson T. Selective serotonin reuptake inhibitors. Antidepressants: From biogenic amines to new mechanisms of action. 2019:135-44.
  25. Jannini TB, Lorenzo GD, Bianciardi E, Niolu C, Toscano M, Ciocca G, et al. Off-label uses of selective serotonin reuptake inhibitors (SSRIs). Current neuropharmacology. 2022;20(4):693.
  26. Caldara M, Marmiroli N. Antimicrobial Properties of Antidepressants and Antipsychotics-Possibilities and Implications. Pharmaceuticals (Basel, Switzerland). 2021;14(9).
  27. Khan H, Rohondia S, Sabry Z, Zalavadiya N, Dou Q. Increasing opportunities of drug repurposing for treating breast cancer by the integration of molecular, histological, and systemic approaches. 2020. p. 121-72.
  28. MacDonald GJ, Bartolomé JM. A decade of progress in the discovery and development of 'atypical' antipsychotics. Progress in medicinal chemistry. 2010;49:37-80.
  29. Włodarczyk A, Szarmach J, Cubała WJ, Wiglusz MS. Benzodiazepines in combination with antipsychotic drugs for schizophrenia: GABA-ergic targeted therapy. Psychiatria Danubina. 2017;29(Suppl 3):345-8.
  30. Flores-Treviño S. Antimicrobial Resistance and Hospital- and Community-Associated Infections. Antibiotics (Basel, Switzerland). 2025;14(5).
  31. Shariati A, Dadashi M, Chegini Z, van Belkum A, Mirzaii M, Khoramrooz SS, et al. The global prevalence of Daptomycin, Tigecycline, Quinupristin/Dalfopristin, and Linezolid-resistant Staphylococcus aureus and coagulase-negative staphylococci strains: a systematic review and meta-analysis. Antimicrobial resistance and infection control. 2020;9(1):56.
  32. Matheou A, Abousetta A, Pascoe AP, Papakostopoulos D, Charalambous L, Panagi S, et al. Antibiotic Use in Livestock Farming: A Driver of Multidrug Resistance? Microorganisms. 2025;13(4).
  33. Abate TA, Birhanu AG. Antibiotic Use in Livestock and Environmental Antibiotic Resistance: A Narrative Review. Environmental health insights. 2025;19:11786302251357775.
  34. Ugurel E, Turgut-Balik D. Synergistic combination of carvedilol, amlodipine, amitriptyline, and antibiotics as an alternative treatment approach for the susceptible and multidrug-resistant A. baumannii infections via drug repurposing. European Journal of Clinical Microbiology & Infectious Diseases. 2023;42(9):1063-72.
  35. de S Machado C, Da Rosa TF, Serafin MB, Bottega A, Coelho SS, Foletto VS, et al. In vitro evaluation of the antibacterial activity of amitriptyline and its synergistic effect with ciprofloxacin, sulfamethoxazole–trimethoprim, and colistin as an alternative in drug repositioning. Medicinal Chemistry Research. 2020;29:166-77.
  36. Ahmed SA, Jordan RL, Isseroff RR, Lenhard JR. Potential Synergy of Fluoxetine and Antibacterial Agents Against Skin and Soft Tissue Pathogens and Drug-Resistant Organisms. Antibiotics. 2024;13(12):1165.
  37. Foletto VS, da Rosa TF, Serafin MB, Bottega A, Franco LN, de Paula BR, et al. Repositioning of antidepressant drugs and synergistic effect with ciprofloxacin against multidrug-resistant bacteria. World Journal of Microbiology and Biotechnology. 2021;37:1-9.
  38. Foletto VS, Serafin MB, Bottega A, da Rosa TF, Machado CdS, Coelho SS, et al. Repositioning of fluoxetine and paroxetine: study of potential antibacterial activity and its combination with ciprofloxacin. Medicinal Chemistry Research. 2020;29:556-63.
  39. Hussein M, Schneider-Futschik EK, Paulin OK, Allobawi R, Crawford S, Zhou QT, et al. Effective strategy targeting polymyxin-resistant gram-negative pathogens: Polymyxin B in combination with the selective serotonin reuptake inhibitor sertraline. ACS Infectious Diseases. 2020;6(6):1436-50.
  40. Krzyżek P, Franiczek R, Krzyżanowska B, Łaczmański Ł, Migdał P, Gościniak G. In Vitro Activity of Sertraline, an Antidepressant, Against Antibiotic-Susceptible and Antibiotic-Resistant Helicobacter pylori Strains. Pathogens. 2019;8(4):228.
  41. Serafin MB, Bottega A, Foletto VS, Rosa TFd, Rampelotto RF, Carvalho FA, et al. Synergistic effect of sertraline and disulfiram against multidrug resistant bacteria as a new alternative to drug repositioning. Brazilian Journal of Pharmaceutical Sciences. 2020;56:e18089.
  42. Rosa TFd, Machado CdS, Serafin MB, Bottega A, Coelho SS, Foletto VS, et al. Repurposing of escitalopram oxalate and clonazepam in combination with ciprofloxacin and sulfamethoxazole–trimethoprim for treatment of multidrug-resistant microorganisms and evaluation of the cleavage capacity of plasmid DNA. Canadian Journal of Microbiology. 2021;67(8):599-612.
  43. da Rosa TF, Serafin MB, Foletto VS, Franco LN, de Paula BR, Fuchs LB, et al. Repositioning of Benzodiazepine Drugs and Synergistic Effect with Ciprofloxacin Against ESKAPE Pathogens. Current microbiology. 2023;80(5):160.
  44. Keleş GT, Kurutepe S, Tok D, Gazi H, Dinç G. Comparison of antimicrobial effects of dexmedetomidine and etomidate-lipuro with those of propofol and midazolam. European journal of anaesthesiology. 2006;23(12):1037-40.
  45. Zolotareva D, Zazybin A, Belyankova Y, Bayazit S, Dauletbakov A, Seilkhanov T, et al. Heterocyclic Antidepressants with Antimicrobial and Fungicide Activity. Molecules [Internet]. 2025; 30(5).
  46. Ait Chait Y, Mottawea W, Tompkins TA, Hammami R. Unravelling the antimicrobial action of antidepressants on gut commensal microbes. Sci Rep. 2020;10(1):17878.
  47. Rukavishnikov G, Leonova L, Kasyanov E, Leonov V, Neznanov N, Mazo G. Antimicrobial activity of antidepressants on normal gut microbiota: Results of the in vitro study. Frontiers in behavioral neuroscience. 2023;17:1132127.
  48. Burin R, Shah DH. Phenelzine and Amoxapine Inhibit Tyramine and d-Glucuronic Acid Catabolism in Clinically Significant Salmonella in A Serotype-Independent Manner. Pathogens (Basel, Switzerland). 2021;10(4).
  49. Wang J, Sha J, Strong E, Chopra Ashok K, Lee S. FDA-Approved Amoxapine Effectively Promotes Macrophage Control of Mycobacteria by Inducing Autophagy. Microbiology spectrum. 2022;10(5):e02509-22.
  50. Gaurav A, Bakht P, Saini M, Pandey S, Pathania R. Role of bacterial efflux pumps in antibiotic resistance, virulence, and strategies to discover novel efflux pump inhibitors. Microbiology (Reading, England). 2023;169(5).
  51. Wei P, Kaatz GW, Kerns RJ. Structural differences between paroxetine and femoxetine responsible for differential inhibition of Staphylococcus aureus efflux pumps. Bioorganic & medicinal chemistry letters. 2004;14(12):3093-7.
  52. Munoz-Bellido J, Munoz-Criado S, Garcıa-Rodrıguez J. Antimicrobial activity of psychotropic drugs: selective serotonin reuptake inhibitors. International journal of antimicrobial agents. 2000;14(3):177-80.
  53. Bohnert JA, Szymaniak-Vits M, Schuster S, Kern WV. Efflux inhibition by selective serotonin reuptake inhibitors in Escherichia coli. Journal of antimicrobial chemotherapy. 2011;66(9):2057-60.
  54. Bohnert JA, Szymaniak-Vits M, Schuster S, Kern WVJJoac. Efflux inhibition by selective serotonin reuptake inhibitors in Escherichia coli. 2011;66(9):2057-60.
  55. Li L, Kromann S, Olsen JE, Svenningsen SW, Olsen RH. Insight into synergetic mechanisms of tetracycline and the selective serotonin reuptake inhibitor, sertraline, in a tetracycline-resistant strain of Escherichia coli. The Journal of Antibiotics. 2017;70(9):944-53.
  56. Holmes AR, Keniya MV, Ivnitski-Steele I, Monk BC, Lamping E, Sklar LA, et al. The monoamine oxidase A inhibitor clorgyline is a broad-spectrum inhibitor of fungal ABC and MFS transporter efflux pump activities which reverses the azole resistance of Candida albicans and Candida glabrata clinical isolates. Antimicrobial agents and chemotherapy. 2012;56(3):1508-15.
  57. Grimsey EM, Fais C, Marshall RL, Ricci V, Ciusa ML, Stone JW, et al. Chlorpromazine and amitriptyline are substrates and inhibitors of the AcrB multidrug efflux pump. MBio. 2020;11(3):10.1128/mbio. 00465-20.
  58. Kashi M, Noei M, Chegini Z, Shariati A. Natural compounds in the fight against Staphylococcus aureus biofilms: a review of antibiofilm strategies. Frontiers in pharmacology. 2024;15:1491363.
  59. Ahmed EI, Alhuwaydi AM, Taha AE, Abouelkheir M. Anti-Candidal Activity of Reboxetine and Sertraline Antidepressants: Effects on Pre-Formed Biofilms. Antibiotics (Basel, Switzerland). 2023;12(5).
  60. Rajasekharan SK, Lee JH, Lee J. Aripiprazole repurposed as an inhibitor of biofilm formation and sterol biosynthesis in multidrug-resistant Candida albicans. International journal of antimicrobial agents. 2019;54(4):518-23.
  61. Caldara M, Marmiroli N. Tricyclic antidepressants inhibit Candida albicans growth and biofilm formation. International journal of antimicrobial agents. 2018;52(4):500-5.
  62. Moraes DC, Ferreira-Pereira A. Insights on the anticandidal activity of non-antifungal drugs. Journal de Mycologie Médicale. 2019;29(3):253-9.
  63. Tozar T, Nastasa V, Stoicu A, Chifiriuc MC, Popa M, Kamerzan C, et al. In vitro antimicrobial efficacy of laser exposed chlorpromazine against Gram-positive bacteria in planktonic and biofilm growth state. Microbial pathogenesis. 2019;129:250-6.
  64. Endo TH, Santos MHM, Scandorieiro S, Gonçalves BC, Vespero EC, Perugini MRE, et al. Selective Serotonin Reuptake Inhibitors: Antimicrobial Activity Against ESKAPEE Bacteria and Mechanisms of Action. Antibiotics (Basel, Switzerland). 2025;14(1).
  65. de Andrade Neto JB, Josino MAA, da Silva CR, de Sousa Campos R, do Nascimento FBSA, Sampaio LS, et al. A mechanistic approach to the in-vitro resistance modulating effects of fluoxetine against meticillin resistant Staphylococcus aureus strains. Microbial Pathogenesis. 2019;127:335-40.
  66. Rácz B, Spengler G. Repurposing Antidepressants and Phenothiazine Antipsychotics as Efflux Pump Inhibitors in Cancer and Infectious Diseases. 2023;12(1):137.
  67. Munoz-Bellido JL, Munoz-Criado S, Garcìa-Rodrìguez JA. Antimicrobial activity of psychotropic drugs: selective serotonin reuptake inhibitors. International journal of antimicrobial agents. 2000;14(3):177-80.
  68. Sjöstedt P, Enander J, Isung J. Serotonin Reuptake Inhibitors and the Gut Microbiome: Significance of the Gut Microbiome in Relation to Mechanism of Action, Treatment Response, Side Effects, and Tachyphylaxis. Frontiers in psychiatry. 2021;12:682868.
  69. McGovern AS, Hamlin AS, Winter G. A review of the antimicrobial side of antidepressants and its putative implications on the gut microbiome. The Australian and New Zealand journal of psychiatry. 2019;53(12):1151-66.
  70. Crane JK, Salehi M, Alvarado CL. Psychoactive Drugs Induce the SOS Response and Shiga Toxin Production in Escherichia Toxins. 2021;13(7).
  71. Vasskog T, Anderssen T, Pedersen-Bjergaard S, Kallenborn R, Jensen E. Occurrence of selective serotonin reuptake inhibitors in sewage and receiving waters at Spitsbergen and in Norway. Journal of chromatography A. 2008;1185(2):194-205.
  72. Arnnok P, Singh RR, Burakham R, Pérez-Fuentetaja A, Aga DS. Selective Uptake and Bioaccumulation of Antidepressants in Fish from Effluent-Impacted Niagara River. Environmental science & technology. 2017;51(18):10652-62.
Medical Journal of Mashhad university of Medical Sciences
Volume 69, Issue 4
May 2026
Pages 463-475

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