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Volume 72, Issue 10

Analysis of possible pathways on the mechanism of action of minocycline and doxycycline against strains of spp. resistant to fluconazole No Access

Abstract

Species of the genus characterized as commensals of the human microbiota, are opportunistic pathogens capable of generating various types of infections with high associated costs. Considering the limited pharmacological arsenal and the emergence of antifungal-resistant strains, the repositioning of drugs is a strategy used to search for new therapeutic alternatives, in which minocycline and doxycycline have been evaluated as potential candidates. Thus, the objective was to evaluate the antifungal activity of two tetracyclines, minocycline and doxycycline, and their possible mechanism of action against fluconazole-resistant strains of spp. The sensitivity test for antimicrobials was performed using the broth microdilution technique, and the pharmacological interaction with fluconazole was also analysed using the checkerboard method. To analyse the possible mechanisms of action, flow cytometry assays were performed. The minimum inhibitory concentration obtained was 4–427 µg ml for minocycline and 128–512 µg ml for doxycycline, and mostly indifferent and additive interactions with fluconazole were observed. These tetracyclines were found to promote cellular alterations that generated death by apoptosis, with concentration-dependent reactive oxygen species production and reduced cell viability. Therefore, minocycline and doxycycline present themselves as promising study molecules against spp.

  • Received:
  • Accepted:
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Keyword(s): Candida spp. , doxycycline , flow cytometry and minocycline
© 2023 The Authors
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/content/journal/jmm/10.1099/jmm.0.001759
2023-10-06
2024-04-28
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References

  1. Rayens E, Norris KA. Prevalence and healthcare burden of fungal infections in the United States, 2018. Open Forum Infect Dis 2022; 9:ofab593 [View Article] [PubMed]
     [Google Scholar]
  2. Romo JA, Kumamoto CA. On Commensalism of Candida. J Fungi 2020; 6:16 [View Article]
     [Google Scholar]
  3. Ré ACS, Martins JF, Cunha-Filho M, Gelfuso GM, Aires CP et al. New perspectives on the topical management of recurrent candidiasis. Drug Deliv Transl Res 2021; 11:1568–1585 [View Article] [PubMed]
     [Google Scholar]
  4. Seyoum E, Bitew A, Mihret A. Distribution of Candida albicans and non-albicans Candida species isolated in different clinical samples and their in vitro antifungal suscetibity profile in ethiopia. BMC Infect Dis 2020; 20:231 [View Article] [PubMed]
     [Google Scholar]
  5. El-Ganiny AM, Kamel HA, Yossef NE, Mansour B, El-Baz AM. Repurposing pantoprazole and haloperidol as efflux pump inhibitors in azole resistant clinical Candida albicans and non-albicans isolates. Saudi Pharm J 2022; 30:245–255 [View Article] [PubMed]
     [Google Scholar]
  6. Bhattacharya S, Sae-Tia S, Fries BC. Candidiasis and mechanisms of antifungal resistance. Antibiotics 2020; 9:1–19 [View Article] [PubMed]
     [Google Scholar]
  7. Kaul G, Shukla M, Dasgupta A, Chopra S. Update on drug-repurposing: is it useful for tackling antimicrobial resistance?. Future Microbiol 2019; 14:829–831 [View Article] [PubMed]
     [Google Scholar]
  8. Miró-Canturri A, Ayerbe-Algaba R, Smani Y. Drug repurposing for the treatment of bacterial and fungal infections. Front Microbiol 2019; 10:41 [View Article] [PubMed]
     [Google Scholar]
  9. Saivin S, Houin G. Clinical pharmacokinetics of doxycycline and minocycline. Clin Pharmacokinet 1988; 15:355–366 [View Article] [PubMed]
     [Google Scholar]
  10. Castillo JRE de Tetracyclines. Antimicrob Ther Vet Med 2013; 15:257–268 [View Article]
     [Google Scholar]
  11. Carris NW, Pardo J, Montero J, Shaeer KM. Minocycline as a substitute for doxycycline in targeted scenarios: a systematic review. Open Forum Infect Dis 2015; 2:ofv178 [View Article] [PubMed]
     [Google Scholar]
  12. Francini E, Miano ST, Fiaschi AI, Francini G. Doxycycline or minocycline may be a viable treatment option against SARS-CoV-2. Med Hypotheses 2020; 144:110054 [View Article] [PubMed]
     [Google Scholar]
  13. Clinical Laboratory Standard Institute-CLSI M27-A3 Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts 2008
     [Google Scholar]
  14. Clinical Laboratory Standard Institute-CLSI M27-S4 Reference Method For Broth Dilution Antifungal Susceptibility Testing of Yeasts; Fourth Informational Supplement 2012
     [Google Scholar]
  15. Odds FC. Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother 2003; 52:1 [View Article] [PubMed]
     [Google Scholar]
  16. Jorge P, Grzywacz D, Kamysz W, Lourenço A, Pereira MO. Searching for new strategies against biofilm infections: colistin-AMP combinations against Pseudomonas aeruginosa and Staphylococcus aureus single- and double-species biofilms. PLoS One 2017; 12:e0174654 [View Article] [PubMed]
     [Google Scholar]
  17. Rocha da Silva C, Sá LG do AV, dos Santos EV, Ferreira TL, Coutinho T do NP et al. Evaluation of the antifungal effect of chlorogenic acid against strains of Candida spp. resistant to fluconazole: apoptosis induction and in silico analysis of the possible mechanisms of action. J Med Microbiol 2022; 71:1–17 [View Article]
     [Google Scholar]
  18. da Silva CR, de Andrade Neto JB, Sidrim JJC, Angelo MRF, Magalhães HIF et al. Synergistic effects of amiodarone and fluconazole on Candida tropicalis resistant to fluconazole. Antimicrob Agents Chemother 2013; 57:1691–1700 [View Article] [PubMed]
     [Google Scholar]
  19. Neto JBA, da Silva CR, Neta MAS, Campos RS, Siebra JT et al. Antifungal activity of naphthoquinoidal compounds in vitro against fluconazole-resistant strains of different Candida species: a special emphasis on mechanisms of action on Candida tropicalis. PLoS One 2014; 9:e93698 [View Article] [PubMed]
     [Google Scholar]
  20. Miloshev G, Mihaylov I, Anachkova B. Application of the single cell gel electrophoresis on yeast cells. Mutat Res 2002; 513:69–74 [View Article] [PubMed]
     [Google Scholar]
  21. Collins AR. The comet assay for DNA damage and repair: principles, applications, and limitations. Mol Biotechnol 2004; 26:249–261 [View Article] [PubMed]
     [Google Scholar]
  22. Hendrickson JA, Hu C, Aitken SL, Beyda N. Antifungal resistance: a concerning trend for the present and future. Curr Infect Dis Rep 2019; 21:1–8 [View Article] [PubMed]
     [Google Scholar]
  23. Logan A, Wolfe A, Williamson JC. Antifungal resistance and the role of new therapeutic agents. Curr Infect Dis Rep 2022; 24:105–116 [View Article] [PubMed]
     [Google Scholar]
  24. Tan J, Jiang S, Tan L, Shi H, Yang L et al. Antifungal activity of minocycline and azoles against fluconazole-resistant Candida species. Front Microbiol 2021; 12:649026 [View Article] [PubMed]
     [Google Scholar]
  25. Shi W, Chen Z, Chen X, Cao L, Liu P et al. The combination of minocycline and fluconazole causes synergistic growth inhibition against Candida albicans: an in vitro interaction of antifungal and antibacterial agents. FEMS Yeast Res 2010; 10:885–893 [View Article] [PubMed]
     [Google Scholar]
  26. Gao Y, Zhang C, Lu C, Liu P, Li Y et al. Synergistic effect of doxycycline and fluconazole against Candida albicans biofilms and the impact of calcium channel blockers. FEMS Yeast Res 2013; 13:453–462 [View Article] [PubMed]
     [Google Scholar]
  27. Fiori A, Van Dijck P. Potent synergistic effect of doxycycline with fluconazole against Candida albicans is mediated by interference with iron homeostasis. Antimicrob Agents Chemother 2012; 56:3785–3796 [View Article] [PubMed]
     [Google Scholar]
  28. Neuvonen PJ. Interactions with the absorption of tetracyclines. Drugs 1976; 11:45–54 [View Article] [PubMed]
     [Google Scholar]
  29. Davey HM, Hexley P. Red but not dead? Membranes of stressed Saccharomyces cerevisiae are permeable to propidium iodide. Environ Microbiol 2011; 13:163–171 [View Article] [PubMed]
     [Google Scholar]
  30. Zhao H, Oczos J, Janowski P, Trembecka D, Dobrucki J et al. Rationale for the real-time and dynamic cell death assays using propidium iodide. Cytometry 2010; 77A:399–405 [View Article]
     [Google Scholar]
  31. Perrone GG, Tan SX, Dawes IW. Reactive oxygen species and yeast apoptosis. Biochim Biophys Acta 2008; 1783:1354–1368 [View Article] [PubMed]
     [Google Scholar]
  32. Santos ALS, Sodre CL, Valle RS, Silva BA, Abi-Chacra EA et al. Antimicrobial action of chelating agents: repercussions on the microorganism development, virulence and pathogenesis. Curr Med Chem 2012; 19:2715–2737 [View Article] [PubMed]
     [Google Scholar]
  33. Li Y, Sun L, Lu C, Gong Y, Li M et al. Promising antifungal targets against Candida albicans based on ion homeostasis. Front Cell Infect Microbiol 2018; 8:286 [View Article] [PubMed]
     [Google Scholar]
  34. Ramsdale M. Programmed cell death in pathogenic fungi. Biochim Biophys Acta. Mol Cell Res 2008; 1783:1369–1380 [View Article] [PubMed]
     [Google Scholar]
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Analysis of possible pathways on the mechanism of action of minocycline and doxycycline against strains of Candida spp. resistant to fluconazole
J. Med. Microbiol. 72, 001759 (2023); https://doi.org/10.1099/jmm.0.001759
/content/journal/jmm/10.1099/jmm.0.001759
/content/journal/jmm/10.1099/jmm.0.001759
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