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Repositioning of Disulfiram in Association with Vancomycin Against Enterococcus spp. MDR and XDR

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Abstract

The identification of molecules that exhibit potent antibacterial activity and are capable of circumventing resistance mechanisms is an unmet need. The repositioning of approved drugs is considered an advantageous alternative in this case, and has gained prominence. In addition, drug synergism can reduce morbidity and mortality in the treatment of nosocomial infections caused by multi-drug resistant microorganisms (MDR). Whole cell growth inhibition assays were used to define the in vitro antibacterial activity of disulfiram against two standard American Type Culture Collection (ATCC) strains and 35 clinical isolates of vancomycin-resistant enterococci (VRE). The ability of disulfiram to synergize with vancomycin was determined by fractional inhibitory concentration index, preceded by the checkerboard test. The cytotoxicity of drugs alone and in combination was tested against Raw 264.7 cells. Disulfiram exhibited potent antibacterial activity against VRE (MIC 16–64 µg mL−1). Results: Associated with vancomycin, disulfiram it had a reduction in MIC of up to 64 times, with values of 0.5–4 µg mL−1. Vancomycin had a MIC of 128–1024 µg mL−1; combined, reduced this value by up to 124 times (8 µg mL−1), with synergy occurring against all strains. Disulfiram and vancomycin alone and in combination did not show cytotoxicity against the eukaryotic cell line. Based on these results, we suggest that the redirection of disulfiram may be promising in the treatment of infections caused by VRE, since it was able to potentiate the activity of vancomycin against the strains, being able to act as an adjuvant in cases of serious infections caused by Enterococcus.

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References

  1. Alipour M, Rajabi M, Khalili R, Torkamanzadeh P (2021) Prevalence of antibiotic resistance genes among Enterococcus strains isolated from the clinical specimens. Gene Reports 23:101092. https://doi.org/10.1016/j.genrep.2021.101092

    Article  CAS  Google Scholar 

  2. Garcia-Migura L, Willems RJ, Baquero F, Coque TM (2016) Multilevel populationgenetic analysis of vanA and vanB Enterococcus faecium causing nosocomialoutbreaks in 27 countries (1986–2012). J Antimicrob Chemother 71:3351–3366. https://doi.org/10.1093/jac/dkw312

    Article  CAS  PubMed  Google Scholar 

  3. Chiang HY, Perencevich EN, Nair R et al (2017) Incidence and outcomes associated with infections caused by vancomycin-resistant enterococci in the United States: systematic literature review andmeta-analysis. Infect Control Hosp Epidemiol 38:203–215. https://doi.org/10.1017/ice.2016.254

    Article  PubMed  Google Scholar 

  4. WHO/CDC/ICBDSR. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Geneva: World Health Organization; 2017.Available at: http://www.who.int/medicines/publications/global-priority-list-antibiotic-resistant-bacteria/en/ [accessed 10.06.2021].

  5. Serafin MB, Hörner R (2018) Drug repositioning, a new alternative in infectious diseases. Braz J Infec Dis 22:252–256. https://doi.org/10.1016/j.bjid.2018.05.007

    Article  Google Scholar 

  6. Foletto VS, da Rosa TF, Serafin MB et al (2021) Repositioning of non-antibiotic drugs as an alternative to microbial resistance: a systematic review. Int J Antimicrob Agents 58(3):106380. https://doi.org/10.1016/j.ijantimicag.2021.106380

    Article  CAS  PubMed  Google Scholar 

  7. Yeu Y, Yoon Y, Park S (2015) Protein localization vector propagation: a method for improving the accuracy of drug repositioning. Mol Bio Syst 11:2096–2102. https://doi.org/10.1039/C5MB00306G

    Article  CAS  Google Scholar 

  8. ** G, Wong S (2014) Toward better drug repositioning: prioritizing and integrating existing methods into efficient pipelines. Drug Discov Today 19:637–644. https://doi.org/10.1016/j.drudis.2013.11.005

    Article  PubMed  Google Scholar 

  9. Triscott J, Lee CK et al (2012) Disulfiram, a drug widely used to control alcoholism, suppressesself-renewal of glioblastoma and overrides resistance to temozolomide. Oncotarget 3:1112–1123. https://doi.org/10.18632/oncotarget.604

    Article  PubMed  PubMed Central  Google Scholar 

  10. Long TE (2017) Repurposing thiram and disulfiram as antibacterial agents for multidrug-resistant Staphylococcus aureus infections. Antimicrob Agents Chemother 61:898–917. https://doi.org/10.1128/AAC.00898-17

    Article  Google Scholar 

  11. Velasco-García R, Zaldívar-Machorro VJ, Mújica-Jiménez C et al (2006) Disulfiram irreversibly aggregates betaine aldehyde dehydrogenase - A potential target for antimicrobial agents against Pseudomonas aeruginosa. Biochem Biophys Res Commun 341:408–415. https://doi.org/10.1016/j.bbrc.2006.01.003

    Article  CAS  PubMed  Google Scholar 

  12. Horita Y, Takii T, Yagi T et al (2012) Antitubercular activity of disulfiram, an antialcoholism drug, against multidrug- and extensively drug-resistant Mycobacterium tuberculosis isolates. Antimicrob Agents Chemother 56:4140–4145. https://doi.org/10.1128/AAC.06445-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gonzáles PR, Pesesky MW, Bouley R et al (2015) Synergistic, collaterally sensitive β-lactam combinations suppress resistance in MRSA. Nat Chem Biol 11:855–861. https://doi.org/10.1038/nchembio.1911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Foletto VS, Serafin MB, Bottega A et al (2020) Repositioning of fluoxetine and paroxetine: study of potential antibacterial activity and its combination with ciprofloxacin. Med Chem Res 29:556–563. https://doi.org/10.1007/s00044-020-02507-6

    Article  CAS  Google Scholar 

  15. Da Rosa TF, Machado CS, Serafin MB et al (2021) 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. Can J Microbiol 67(8):599–612. https://doi.org/10.1139/cjm-2020-0546

    Article  CAS  PubMed  Google Scholar 

  16. Thakare R, Shukla M, Kaul G et al (2019) Repurposing disulfiram for treatment of Staphylococcus aureus infections. Int J Antimicrob Agents 53:709–715. https://doi.org/10.1016/j.ijantimicag.2019.03.024

    Article  CAS  PubMed  Google Scholar 

  17. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing, Clinical and Laboratory Standards Institute, Wayne, PA (2019), CLSI supplement M100.

  18. Magiorakos AP, Srinivasan A, Carey RB et al (2011) Multidrug-resistant, extensively drug resistantand pandrug-resistant bacteria: an international expert pro-posal for interim standard definitions for acquired resistance. Clin Microbiol Infect 18:268e81. https://doi.org/10.1111/j.1469-0691.2011.03570.x

    Article  Google Scholar 

  19. Clinical and Laboratory Standards Institute. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard M07–A9. Wayne, USA (2012), CLSI.

  20. Lorian V (2005) Antibiotics in Laboratory Medicine, 5th edn. Lippincott Williams & Wilkins, Philadelphia, PA, pp 365–441

    Google Scholar 

  21. 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. https://doi.org/10.1186/1476-0711-11-18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Twentyman PR, Luscombe M (1987) A study of some variables in a tetrazolium dye (MTT) based assay for cell growth and chemosensitivity. Br J Cancer 56:279–285. https://doi.org/10.1038/bjc.1987.190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yeo CY, Sim JH, Khoo CH et al (2013) Pathogenic Gram positive bacteria are highly sensitive to triphenylphosphane gold (Oalkylthiocarbamates), Ph3PAu[SC(OR)=N(p-tolyl)] (R=Me, Et and iPr). Gold Bull 46:145–152. https://doi.org/10.1007/s13404-013-0091-z

    Article  CAS  Google Scholar 

  24. Loi VV, Rossius M, Antelmann H (2015) Redox regulation by reversible protein S-thiolation in bacteria. Front Microbiol 6(187):1–22. https://doi.org/10.3389/fmicb.2015.00187

    Article  Google Scholar 

  25. Takii T, Horita Y, Kuroishi R, Chibal T (2012) The potential therapeutic usage of dithiocarbamate sugar derivatives for multi-drug resistant tuberculosis. Understanding Tuberculosis. https://doi.org/10.5772/29628

    Article  Google Scholar 

  26. Cvek B (2013) Comment on cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells. Br J Cancer 2013(4):993. https://doi.org/10.1038/bjc.2013.18

    Article  CAS  Google Scholar 

  27. Zilberberg MD, Shorr AF, Micek ST et al (2014) Multi-drug resistance, inappropriate initial antibiotic therapy and mortality in Gram-negative severe sepsis and septic shock: a retrospective cohort study. Crit Care 18:596. https://doi.org/10.1186/s13054-014-0596-8

    Article  PubMed  PubMed Central  Google Scholar 

  28. Donadio S, Maffioli S, Monciardini P et al (2010) Antibiotic discovery in the twenty-first century: current trends and future perspectives. J Antibiot 63:423–430. https://doi.org/10.1038/ja.2010.62

    Article  CAS  Google Scholar 

  29. Lloyd-Smith P (2017) Controlling for endogeneity in attributable costs of vancomycin-resistant enterococci from a Canadian hospital. Am J Infect Control 45(12):E161–E164. https://doi.org/10.1016/j.ajic.2017.08.044

    Article  PubMed  Google Scholar 

  30. Da Rosa TF, Coelho SS, Foletto VS et al (2020) Alternatives for the treatment of infections caused by ESKAPE pathogens. J Clin Pharm Ther 45:863–887. https://doi.org/10.1111/jcpt.13149

    Article  PubMed  Google Scholar 

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Acknowledgements

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001.

Funding

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001.

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Authors and Affiliations

  1. Programa de Pós-graduação em Ciências Farmacêuticas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil

    Marissa B. Serafin, Vitória S. Foletto, Taciéli F. da Rosa, Angelita Bottega, Sara de Lima Marion, Augusto Dias da Mota & Rosmari Hörner

  2. Área de Ciências da Saúde, Universidade Franciscana, Santa Maria, RS, Brazil

    Altevir Rossato Viana

  3. Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil

    Laísa Nunes Franco, Bruno Rafael de Paula, Luciana Maria Fontanari Krause & Rosmari Hörner

  4. Hospital Universitário de Santa Maria, Santa Maria, RS, Brazil

    Luis Junior Finatto

  5. Departamento de Química, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil

    Manfredo Hörner

Authors
  1. Marissa B. Serafin
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  2. Vitória S. Foletto
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  3. Taciéli F. da Rosa
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Contributions

MBS, VSF, TFR, AB, AVR, LNF, SLM, ADM, BRP, LMFK, LJF, MH and RH: The conception and design of the study, acquisition of data, analysis and interpretation of the data, drafting and critical revision of the manuscript and final approval of the version to be submitted.

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Correspondence to Rosmari Hörner.

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The use of bacterial isolates for clinical research was approved by the Ethics and Research Committee (CEP) of the Federal University of Santa Maria (UFSM), registered under number 38850614.4.0000.5346, opinion number 928,497. Registration in the National System for the Management of Genetic Heritage and Associated Traditional Knowledge (SisGen) was registered under number AE78E18 –UFSM.

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Serafin, M.B., Foletto, V.S., da Rosa, T.F. et al. Repositioning of Disulfiram in Association with Vancomycin Against Enterococcus spp. MDR and XDR. Curr Microbiol 79, 137 (2022). https://doi.org/10.1007/s00284-022-02794-9

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