Abstract
The repositioning of drugs has been shown to be an advantageous alternative for treating diseases caused by multidrug-resistant (MDR) microorganisms. The study aimed to investigate the in vitro antibacterial activity of the antidepressants fluoxetine and paroxetine alone and in combination with the antibacterial ciprofloxacin against standard strains and clinical isolates to explore the repositioning of these drugs in severe bacterial infections. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), tolerance level, fractional inhibitory concentration index (FICI) and interaction of antidepressants with the ciprofloxacin antibiotic were determined using the Checkerboard method against six American Type Culture Collection (ATCC) standard strains and seventy MDR clinical isolates. Both antidepressants showed better antibacterial activity than ciprofloxacin, in addition to being separately bactericidal against all tested Gram-negative and Gram-positive strains. When associated with ciprofloxacin, fluoxetine and paroxetine exhibited significant synergism compared to seventy ciprofloxacin-resistant clinical isolates, demonstrating that these antidepressants were able to increase the antibacterial activity of the antibiotic by eight times. The combination of antidepressants with ciprofloxacin showed relatively better activity against Acinetobacter baumannii, Enterococcus faecium and Klebsiella pneumoniae, strains in which the FICI value obtained was 0.008. The MDR isolates tested in this study ratify the antibacterial properties of the non-antibiotic fluoxetine and paroxetine. In addition, synergism when associated with ciprofloxacin is an alternative for treating serious infections in hospitalized patients. However, additional in vivo studies must be conducted to elucidate the mechanisms of action of these drugs.
Similar content being viewed by others
Code availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
References
Ahmed K, Shaw HV, Koval A, Katanaev VL (2016) A second WNT for old drugs: drug repositioning against WNT-dependent cancers. Cancers 8(7):66
Amaral L, Martins A, Molnar J, Kristiansen JE, Martins M, Viveiros M et al (2010) Phenothiazines, bacterial efflux pumps and targeting the macrophage for enhanced killing of intracellular XDRTB. In Vivo 24(4):409–424
Ashburn TT, Thor KB (2004) Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov 3:673–683
Berdigaliyev N, Aljofan M (2020) An overview of drug discovery and development. Future Med Chem 12(10):939–947
Brown D (2015) Antibiotic resistance breakers: can repurposed drugs fill the antibiotic discovery void? Nat Rev Drug Discov 14(12):821–832
Centers for Disease Control and Prevention (2017) Antibiotic use in the United States: progress and opportunities, Atlanta. https://www.cdc.gov/antibiotic-use/stewardship-report/pdf/stewardship-report.pdf
Clinical and Laboratory Standards Institute (2012) M07-A9 Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 9th edn. Wayne: CLSI document. ISBN: 1-56238-785-5. https://clsi.org/media/1632/m07a10_sample.pdf
Das B, Dash SK, Mandal D, Ghosh T, Chattopadhyay S, Tripathy S et al (2017) Green synthesized silver nanoparticles destroy multidrug resistant bacteria via reactive oxygen species mediated membrane damage. Arab J Chem 10(6):862–876
De Sousa AK, Rocha JE, de Souza TG, de Freitas TS, Ribeiro-Filho J, Coutinho HDM (2018) New roles of fluoxetine in pharmacology: antibacterial effect and modulation of antibiotic activity. Microb Pathog 123:368–371
Foletto VS, Serafin MB, da Rosa TF, Bottega A, Coelho SS, Machado CS et al (2019) Fluoxetine and paroxetine: repositioning as a therapeutic alternative in the treatment of various diseases. Am J Ther 27(5):e547–e551
Gelosa P, Castiglioni L, Camera M, Sironi L (2020) Drug repurposing in cardiovascular diseases: opportunity or hopeless dream? Biochem Pharmacol 177:113894
Hadera M, Mehari S, Basha NS, Amha ND, Berhane Y (2018) Study on antimicrobial potential of selected non-antibiotics and its interaction with conventional antibiotics. UK J Pharm Biosci 6:01–07
Ihara M, Saito S (2020) Drug repositioning for Alzheimer’s disease: finding hidden clues in old drugs. J Alzheimers Dis 74(4):1013–1028
Kaur I (2016) Novel strategies to combat antimicrobial resistance. J Infect Dis Ther 4:4
Konaté K, Mavoungou JF, Lepengué AN, Aworet-Samveny RR, Hilou A, Souza A et al (2012) Antibacterial activity against β-lactamase producing Methicillin and Ampicillin-resistants Staphylococcus aureus: fractional Inhibitory Concentration Index (FICI) determination. Ann Clin Microbiol Antimicrob 11:18
Konreddy AK, Rani GU, Lee K, Choi Y (2019) Recent drug-repurposing-driven advances in the discovery of novel antibiotics. Curr Med Chem 26(28):5363–5388
Lorian V (2005) Antibiotics in laboratory medicine, 5th edn. Lippincott Williams & Wilkins, Philadelphia, pp 365–441
Meibohm B, Derendorf H (2002) Pharmacokinetic/pharmacodynamic studies in drug product development. J Pharm Sci 91(1):18–31
Michael CA, Dominey-Howes D, Labbate M (2014) The antimicrobial resistance crisis: causes, consequences, and management. Front Public Health 2:145
Miró-Canturri A, Ayerbe-Algaba R, Smani Y (2019) Drug repurposing for the treatment of bacterial and fungal infections. Front Microbiol 28(10):41
Morehead MS, Scarbrough C (2018) Emergence of global antibiotic resistance. Prim Care Clin Office Pract 45(3):467–484
Mouton JW, Brown DFJ, Apfalter P, Cantón R, Giske CG, Ivanova M et al (2011) The role of pharmacokinetics/pharmacodynamics in setting clinical MIC breakpoints: the EUCAST approach. Clin Microbiol Infect 18(3):E37-45
Mulani MS, Kamble EE, Kumkar SN, Tawre MS, Pardesi KR (2019) Emerging strategies to combat ESKAPE pathogens in the era of antimicrobial resistance: a review. Front Microbiol 10:539
Munoz-Bellido JL, Munoz-Criado S, Garcìa-Rodrìguez JÁ (2000) Antimicrobial activity of psychotropic drugs selective serotonin reuptake inhibitors. Int J Antimicrob Agents 14(3):177–180
National Committee for Clinical Laboratory Standards (1999) Methods for determining bactericidal activity of antimicrobial agents: approved guideline M26-A. vol. 19; No. 8. NCCLS, Wayne. https://clsi.org/media/1462/m26a_sample.pdf
Neto JBA, Josino MAA, da Silva CR, Campos RS, Nascimento FBSA, Sampaio LS et al (2019) A mechanistic approach to the in-vitro resistance modulating effects of fluoxetine against meticillin resistant Staphylococcus aureus strains. Microb Pathog 127:335–340
Odds FC (2003) Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemoth 52(1):1
Otto RG, van Gorp E, Kloezen W, Meletiadis J, van den Berg S, Mouton JW (2019) An alternative strategy for combination therapy: Interactions between polymyxin B and non-antibiotics. Int J Antimicrob Agents 53(1):34–39
Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR et al (2010) How to improve R&D productivity: the pharmaceutical industry’s grand challenge. Nat Rev Drug Discov 9:203–214
Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A et al (2019) Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 18(1):41–58
Rastelli G, Pellati F, Pinzi L, Gamberini MC (2020) Repositioning natural products in drug discovery. Molecules 25(5):1154
Roca I, Akova M, Baquero F, Carlet J, Cavaleri M, Coenen S et al (2015) The global threat of antimicrobial resistance: science for intervention. New Microbes New Infect 6:22–29
Rodrigues TS, dos Santos AMR, Lima PC, Moura MEB, Goiano PDOL, Fontinele DRS (2018) Resistência bacteriana á antibióticos na Unidade de Terapia Intensiva: Revisão Integrativa. Rev Pre Infec e Saúde 4:7350
Serafin MB, Hörner R (2018) Drug repositioning, a new alternative in infectious diseases. Braz J Infect Dis 22:252–256
Spellberg B, Srinivasan A, Chambers HF (2016) New societal approaches to empowering antibiotic stewardship. JAMA 315(12):1229–1230
Strittmatter SM (2014) Overcoming drug development bottlenecks with repurposing: old drugs learn new tricks. Nat Med 20(6):590–591
Vazquez-Grande G, Kumar A (2015) Optimizing antimicrobial therapy of sepsis and septic shock: focus on antibiotic combination therapy. Semin Respir Crit Care Med 36(1):154–166
Vogt I, Mestres J (2010) Drug-Target Networks. Mol Inform 29:10–14
Wellington EMH, Boxall ABA, Cross P (2013) The role of the natural environment in the emergence of antibiotic resistance in Gram-negative bacteria. Lancet Infect Dis 13(2):155–165
World Health Organization (2015) Global action plan on antimicrobial resistance. World Health Organization, Geneva. https://www.who.int/antimicrobial-resistance/global-action-plan/en/
World Health Organization (2017) Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. World Health Organization, Geneva. https://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/
Xue H, Li J, Xie H, Wang Y (2018) Review of drug repositioning approaches and resources. Int J Biol Sci 14(10):1232–1244
Yang Y, Zhang Z, Li S, Ye X, Li X, He K (2014) Synergy effects of herb extracts: pharmacokinetics and pharmacodynamic basis. Fitoterapia 92:133–147
Yeu Y, Yoon Y, Park S (2015) Protein localization vector propagation: a method for improving accuracy of drug repositioning. Mol Biosyst 11(7):2096–2102
Zheng W, Sun W, Simeonov A (2018) Drug repurposing screens and synergistic drug-combinations for infectious diseases. Br J Pharmacol 175(2):181–191
Funding
This work was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES) under Grant 001.
Author information
Authors and Affiliations
Contributions
VSF contributed to the conception and design of the study, data acquisition, data analysis and interpretation, writing and critical review of the manuscript. TFR, MBS and AB assisted in the design, analysis, interpretation of data and critical review of the manuscript. LNF and BRP performed the collection of clinical samples and isolation of strains. RH participated in the conception and experimental design, analysis and interpretation of data and critical review of the manuscript. All authors read and approved the final article.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no confict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Foletto, V.S., da Rosa, T.F., Serafin, M.B. et al. Repositioning of antidepressant drugs and synergistic effect with ciprofloxacin against multidrug-resistant bacteria. World J Microbiol Biotechnol 37, 53 (2021). https://doi.org/10.1007/s11274-021-03016-3
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11274-021-03016-3