Candidiasis: the problem of finding new etiotropic drugs among organic synthesis products

Cover Page

Cite item

Full Text

Abstract

1043 compounds - products of organic synthesis were screened for antifungal activity on the type strain C. albicans NCTC 885-653 in planktonic culture. In-depth studies of substances with high activity against typical strains of Candida spp. and clinical isolates to identify lead compounds, including on a biofilm model were done. 3 substances were identified that exhibit high antifungal activity (MIC50 - 1.0-2.0; MIC90 - 7.8-31.2), exceeding the effect of the reference drug fluconazole. Thus, representatives of new chemical groups with antifungal activity were identified. A methodology has been developed for searching for compounds with antifungal activity among products of organic synthesis, based on the use of a combination of theoretical, physicochemical, and biological methods. An algorithm for the early stages of preclinical studies of the presence of antifungal activity in newly synthesized compounds using microbiological methods is proposed. It including screening studies for typical strains of yeast micromycetes, in-depth studies of clinical isolates to study the cumulative indicators of sensitivity of a population of strains, and determination of the antifungal activity of compounds on a biofilm model.

About the authors

Valentina V. Novikova

Perm State Pharmaceutical Academy of the Ministry of Health of the Russian Federation

Author for correspondence.
Email: vvnperm@yandex.ru

Doctor of Pharmacy, Associate Professor, Head of the Department of Microbiology

Russian Federation, Perm

Vladimir L. Gein

Perm State Pharmaceutical Academy of the Ministry of Health of the Russian Federation

Email: geinvl48@mail.ru

Doctor of Chemical Sciences, Professor, Head of the Department of General and Organic Chemistry

Russian Federation, Perm

Olga V. Bobrovskaya

Perm State Pharmaceutical Academy of the Ministry of Health of the Russian Federation

Email: bobban@mail.ru

Doctor of Pharmacy, Associate Professor, Professor of the Department of Pharmaceutical Chemistry

Russian Federation, Perm

Natalia A. Pulina

Perm State Pharmaceutical Academy of the Ministry of Health of the Russian Federation

Email: pulina.natalya@pfa.ru

Doctor of Pharmacy, Professor, Head of the Department of Pharmaceutical Technology

Russian Federation, Perm

Nazim M. Igidov

Perm State Pharmaceutical Academy of the Ministry of Health of the Russian Federation

Email: igidov_nazim@mail.ru

Doctor of Pharmacy, Professor of the Department of General and Organic Chemistry

Russian Federation, Perm

Irina P. Rudakova

Perm State Pharmaceutical Academy of the Ministry of Health of the Russian Federation

Email: rudakova@pfa.ru

Doctor of Medical Sciences, Associate Professor, Head of the Department of Physiology

Russian Federation, Perm

References

  1. The burden of serious fungal diseases in Russia / N. Klimko, Y. Kozlova, S. Khostelidi [et al.] // Mycoses. – 2015. T. 58. – C.8-62. doi: 10.1111/myc.12388.
  2. Denning, D. W. Global burden of recurrent vulvovaginal candidiasis: a systematic review / D. W. Denning, M Kneale., J. D. Sobel, R. Rautemaa-Richardson // The Lancet infectious diseases. – 2018. – V. 18. – №11. – P.:339-347. doi: 10.1016/S1473-3099(18)30103-8.
  3. A clinico-mycological spectrum of Superficial Mycoses of the scalp in the paediatric population / F. Zeeshan, F. Uddin, B. Khan [et al.] // Journal of Rawalpindi Medical College - 2020/ – V. 24. – №4. – Р.395-399. doi: 10.37939/jrmc.v24i4/1476.
  4. Kubanov, A. A. The results of the activities of medical organizations providing medical care in the field of dermatovenereology in 2020: work in a pandemic / A. A. Kubanov, E. V. Bogdanova // Bulletin of Dermatology and Venereology. – 2021. – T. 97, No. 4. – S. 8-32. – doi: 10.25208/vdv1261. (In Russ.).
  5. Tackling the emerging threat of antifungal resistance to human health / M. C. Fisher, А.. Alastruey-Izquierdo, J. Berman [et al.] // Nature Reviews Microbiology. – 2022. – Т. 20. – №9. С.:557-571. doi: 10.1038/s41579-022-00720-1.
  6. Threats posed by the fungal kingdom to humans, wildlife, and agriculture / M. C. Fisher, S. J. Gurr, C. A. Cuomo [et al.] // ASM Journals. MBio. – 2020. – V.11. - №3. – Р.e00449-20. doi: 10.1128/mBio.00449-20.
  7. Malova, I. O. Modern features of the clinical course of urogenital candidiasis and analysis of antimycotic sensitivity of fungi of the genus Candida / I. O. Malova, Yu. A. Kuznetsova // Bulletin of Dermatology and Venereology. – 2015. – No. 2. – S. 68–75. (In Russ.).
  8. Arutjunjan, N. S. Kandidoznye vul'vovaginity u zhenshhin v period beremennosti / N. S. Arutjunjan, A. A. Mkrtchjan, P. S. Agafonov. // Problemy medicinskoj mikologii. – 2015. – T. 17, № 2. – S. 40. (In Russ.).
  9. Biofilms formed by isolates from recurrent vulvovaginal candidiasis patients are heterogeneous and insensitive to fluconazole / L. Sherry, R. Kean, E. McKloud [et al.]. // Antimicrobial agents and chemotherapy. – 2017. – Vol. 61, №. 9. – Р. 01065-17.
  10. Prevalence of Candida spp. in cervical-vaginal samples and the in vitro susceptibility of isolates / T. M. Brandolt, G. B. Klafke, C.V. Gonçalves [et al] // Brazilian journal of microbiology. – 2017. – V. 48. – №. 1. – С. 145–150.
  11. Mezhevitinova E.A., Abakarova P.R., Pogosyan S.M. Use of fluconazole in women of reproductive age with vulvovaginal candidiasis. Meditsinskiy sovet = Medical Council. 2018;(13):96-102. DOI: https://doi.org/10.21518/2079-701X-2018-13-96-102. (In Russ.).
  12. Novikova, VV Analysis of the species composition and sensitivity of clinical isolates of Candida spp. to modern antimycotics / V. V. Novikova, S. G. Ezov, A. I. Selivanova // Medical Almanac. – 2017. – No. 2 (47). – S. 138–141. (In Russ.).
  13. Novikova, V. V. Vidovoj sostav izoljatov Sandida spp., vydelennyh iz razlichnyh biomaterialov pacientov g. Permi / V.V. Novikova, E. V. Kosjakova, M. V. Loginova // Vestnik Permskoj gosudarstvennoj farmacevticheskoj akademii. Nauchno-prakticheskaja konferencija s mezhdunarodnym uchastiem «Aktual'nye problemy himicheskoj bezopasnosti v sfere farmacevticheskoj i medicinskoj nauki i praktiki», posvjashhennaja 50-letiju kafedry toksikologicheskoj himii: Sbornik materialov (14 - 15 dekabrja 2022 goda) / otv. red. V.G. Luzhanin. – Perm', PGFA, 2022. – T. 29. – S.281–284. (In Russ.).
  14. Perfect, J. R. The antifungal pipeline: a reality check / J. R. Perfect. // Nature reviews Drug discovery. – 2017. – Vol. 16, №. 9. – Р. 603.
  15. A review on antibacterial, antiviral, and antifungal activity of curcumin / S. Zorofchian Moghadamtousi, H. A. Kadir, P. Hassandarvish [et al.] // BioMed research international. – 2014. – Т. 2014.
  16. Disulphide-reduced psoriasin is a human apoptosis-inducing broad-spectrum fungicide / K. Z. Hein, H. Takahashi, T. Tsumori [et al.]. // Proceedings of the National Academy of Sciences. – 2015. – Т. 112, №. 42. – С. 13039-13044.
  17. Koshevenko, A. S. Synthesis and antifungal activity of new chlorides ,4-thiadiazol-3-ium / A. S. Koshevenko, I. P. Yakovlev, V. N. Yuskovets [et al.] // Chemical-pharmaceutical journal. - 2017. - T. 51, No. 6. - S. 18-20. (In Russ.).
  18. Sphingolipids as targets for treatment of fungal infections / R. Rollin-Pinheiro, A. Singh, E. Barreto-Bergter, M. Del Poeta. // Future Medicinal Chemistry. – 2016. – Vol. 8, №. 12. – P. 1469-1484.
  19. ASP2397: a novel antifungal agent produced by Acremonium persicinum MF-347833 / I. Nakamura, S. Yoshimura, T. Masaki [et al.]. // The Journal of Antibiotics. – 2017. – Vol. 70, №. 1. – P. 45-51.
  20. Novikova, V. V. Search for new antimycotic agents: main trends and problems / V. V. Novikova // Kursk Scientific and Practical Bulletin Man and his health. – 2020. – No. 1. – P. 75–81. – doi: 10.21626/vestnik/2020-1/09. (In Russ.).
  21. Synthesis and antimicrobial activity of methyl 4-aryl-2-{4-[(4,6-dimethylpyrimidin2-yl)sulfamoyl]phenylamino}-4-oxobut-2-enoates and their silver salts / V. L. Gein, O. V. Bobrovskaya, E. A. Mashkina [et al.] // Journal of General Chemistry. – 2020. – T. 90, No. 5. – S. 723-729. – doi: 10.31857/S0044460X20050108. (In Russ.).
  22. Antifungal activity of new derivatives of 4-(het)aryl-2,4-dioxobutanoic acids / V. V. Novikova, N. A. Pulina, F. V. Sobin, K. V. Lipatnikov // Reviews of clinical pharmacology and drug therapy . – 2020. – T. 18, No. 3. – S. 225-228. – doi: 10.17816/RCF183225-228. (In Russ.).
  23. Novikova, V. V. Studying the antifungal activity of a new bromo derivative of 4,5-dihydrofuran-3-carboxylic acid on a biofilm model / V. V. Novikova, D. V. Ivanov, N. M. Igidov // Experimental and Clinical Pharmacology. – 2023. – T. 86, No. 2. - S. 14-17. – doi: 10.30906/0869-2092-2023-86-2-14-17. (In Russ.).
  24. Guidelines for conducting preclinical studies of medicines / Scientific Center for Expertise of Medicinal Products of the Ministry of Health and Social Development of Russia. Volume Part 1. - Moscow: Grif and K, 2012. - 944 p. – ISBN 978-5-8125-1466-3. (In Russ.).
  25. EUCAST Definitive Document EDef 7.3.2: Method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for yeasts. Available at: https://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/AFST/Files/EUCAST_E_Def_7.3.2_Yeast_testing_definitive_revised_2020.pdf.
  26. Opredelenie chuvstvitel'nosti mikroorganizmov k antimikrobnym preparatam. Klinicheskie rekomendacii, 2021, 225 s. Rezhim dostupa: http:// ww.antibiotic.ru/files/321/clrec-dsma2021.pdf. (In Russ.).
  27. Novikova, V.V., Yakimova, E.V., Gorbushina, A.D. Investigation of new products of organic synthesis for antifungal activity against yeast fungi: substantiation of the choice of test conditions. Bulletin of the Voronezh State University. Series: Chemistry. Biology. Pharmacy. - 2022. – No. 3. – P. 105–112. (In Russ.).
  28. Metodicheskie rekomendacii po izucheniju obshhetoksicheskogo dejstvija farmakologicheskih sredstv : utverzhdeny 25.12.1997. // Vestnik farmakopejnogo komiteta. – 1998. – № 1. – S. 27–32. (In Russ.).
  29. Izmerov, N. F. Parametry toksikometrii promyshlennyh jadov pri odnokratnom vozdejstvii (spravochnik) / N. F. Izmerov, I. V. Sanockij, K. K. Sidorov. – Moskva : Medicina, 1977. – S. 196-197. (In Russ.).
  30. GOST 32419-2013. Klassifikacija opasnosti himicheskoj produkcii. Obshhie trebovanija: nacional'nyj standart Rossijskoj Federacii : izdanie oficial'noe : utverzhden i vveden v dejstvie Prikazom Federal'nogo agentstva po tehnicheskomu regulirovaniju i metrologii ot 22 nojabrja 2013 g. № 833-st : vveden vpervye: data vvedenija 2014-08-01 / razrabotan FGUP «VNICSMV». – Moskva: Standartinform, 2014. – 25 c. (In Russ.).
  31. IOI A. C. Soglasovannaja na global'nom urovne sistema klassifikacij opasnosti i markirovki himicheskoj produkcii (SGS). – Izd. 6-oe, peresmotr. – N'ju-Jork, Zheneva: Organizacija ob#edinennyh nacij, 2015. – ST/SG 30/Rev. 6.
  32. National Library of Medicine. ChemIDplus. Bethesda, 1994.: sajt. – URL: https://chem.nlm.nih.gov/chemidplus/name/fluconazole

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig. 1. Efficacy of the leading compounds against antimycotic-resistant strains of Candida spp. and Candida non-albicans compared with fluconazole, %

Download (47KB)
Indexing metadata

Copyright (c) 2023 Novikova V.V., Gein V.L., Bobrovskaya O.V., Pulina N.A., Igidov N.M., Rudakova I.P.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
 


Согласие на обработку персональных данных

 

Используя сайт https://journals.rcsi.science, я (далее – «Пользователь» или «Субъект персональных данных») даю согласие на обработку персональных данных на этом сайте (текст Согласия) и на обработку персональных данных с помощью сервиса «Яндекс.Метрика» (текст Согласия).