Original Article

Synthesis, Cytotoxicity Evaluation, and Antifungal Activity of Novel Nitroglycerin Derivatives against Clinical Candida albi-cans Isolates

Abstract

Background: Candida albicans remains the main cause of candidiasis in most clinical settings. Available drugs for candidiasis treatment have many side effects. In this work, novel nitroglycerin derivatives were synthesized and their cytotoxic and antifungal effects evaluated against fluconazole susceptible and resistant clinical C. albicans isolates.

Methods: This experimental study was performed in Tehran University of Medical Sciences and Baqiatallah University of Medical Sciences, Tehran, Iran between Feb to Dec 2019. The in vitro activities of two novel nitroglycerin derivatives (1b and 2b) against 25 clinical fluconazole-susceptible and resistant C. albicans isolates and four standard C. albicans strains were determined according to CLSI reference M27-A3 documents. The cytotoxicity of chemical compounds was investigated near the SNL76/7 cells by colorimetric assay. Real-time PCRs were performed to evaluate the alterations in the regulation of ERG11 and CDR1 genes under nitroglycerin derivatives-treated and untreated conditions.

Results: The derivatives 1b and 2b exhibited potent antifungal activity against C. albicans isolates; MICs and MFCs varied from 18 μg/ml to 72 μg/ml and 36 μg/ml to 144 μg/ml, respectively. The cell viability evaluation demonstrated that both chemical compounds are safe within 24h. The nitroglycerin derivatives were able to reduce the transcription level of CDR1 and ERG11 genes in all susceptible and resistant C. albicans isolates.

Conclusion: Considering the potential and efficacy of these compounds against clinical C. albicans isolates, the complementary in vivo and clinical trials should be investigated.

1. Naglik JR, Richardson JP, Moyes DL (2014). Candida albicans pathogenicity and epitheli-al immunity. PLoS Pathog, 10(8): e1004257.
2. Vaezi A, Fakhim H, Khodavaisy S, et al (2017). Epidemiological and mycological characteristics of candidemia in Iran: A systematic review and meta-analysis, J My-col Med, 27(2):146-152.
3. Pappas PG, Lionakis MS, Arendrup MC, et al (2018). Invasive candidiasis. Nat Rev Dis Primers, 4:18026.
4. Allen D, Wilson D, Drew R, et al (2015). Azole antifungals: 35 years of invasive fungal infection management. Expert Rev Anti Infect Ther, 13(6):787-98.
5. Stover KR, Farley JM, Kyle PB, et al (2014). Cardiac toxicity of some echinocandin antifungals. Expert opinion on drug safe-ty. Expert Opin Drug Saf, 13(1):5-14.
6. Bicanic T, Bottomley C, Loyse A, et al (2015). Toxicity of amphotericin B deox-ycholate-based induction therapy in pa-tients with HIV-associated cryptococcal meningitis. Antimicrob Agents Chemother, 50(9): 2846–2856.
7. Pfaller M, Diekema D (2012). Progress in antifungal susceptibility testing of Candida spp. by use of Clinical and Laboratory Standards Institute broth microdilution methods, 2010 to 2012. J Clin Microbiol, 50(9):2846-2856.
8. Palmeira-de-Oliveira A, Ramos AR, Gaspar C, et al (2012). In vitro anti-Candida ac-tivity of lidocaine and nitroglycerin: alone and combined. Infect Dis Obstet Gynecol, 2012:727248.
9. Institute CaLS (2009). Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard-3rd ed. Document M27-A3. JCM, 47: 2766-72 .
10. Institute CaLS (2014). Reference method for broth dilution antifungal susceptibility testing of yeasts; 4thinformational sup-plement. Document M27-S4. Rev. Inst Med Trop S Paulo, 56:31-6.
11. Cantón E, Pemán J, Viudes A, et al (2003). Minimum fungicidal concentrations of amphotericin B for bloodstream Candida species. Diagn Microbiol Infect Dis, 45(3):203-6.
12. Wisplinghoff H, Bischoff T, Tallent SM, et al (2004). Nosocomial bloodstream infec-tions in US hospitals: analysis of 24,179 cases from a prospective nationwide sur-veillance study. Arch Clin Infect Dis, 39(3):309-17.
13. Sellami A, Sellami H, Neji S, et al (2011). An-tifungal susceptibility of bloodstream Candida isolates in Sfax hospital: Tunisia. Mycopathologia, 171(6):417-22.
14. Miceli MH, Díaz JA, Lee SA (2011). Emerg-ing opportunistic yeast infections. Lancet Infect Dis, 11(2):142-51.
15. Khodavaisy S, Badali H, Meis JF, et al (2020). Comparative in vitro activities of seven antifungal drugs against clinical iso-lates of Candida parapsilosis complex. J My-col Med, 30(3): 100968
16. Stylianou M, Kulesskiy E, Lopes JP, et al (2014). Antifungal application of nonanti-fungal drugs. Antimicrob Agents Chemother, 58(2):1055-62.
17. Kalayci S (2016). Antimicrobial properties of various non-antibiotic drugs against mi-croorganisms. Journal of Bioanalysis and Bio-medicine, 8(4):1120-1124.
18. Kruszewska H, Zareba T, Tyski S (2008). Examination of antibacterial and antifun-gal activity of selected non-antibiotic products. Acta Pol Pharm, 65(6):779-82.
19. Nyilasi I (2010). Effect of different statins on the antifungal activity of polyene an-timycotics. Acta Biologica Szegediensis, 54(1):33-6.
20. Rosenblatt J, Reitzel R, Dvorak T, et al (2013). Glyceryl trinitrate complements citrate and ethanol in a novel antimicrobi-al catheter lock solutionto eradicate bio-film organisms. Antimicrob Agents Chemoth-er, 57(8): 3555–3560.
21. Reitzel RA, Rosenblatt J, Hirsh-Ginsberg C, et al (2016). In vitro assessment of the an-timicrobial efficacy of optimized nitro-glycerin-citrate-ethanol as a nonantibiotic, antimicrobial catheter lock solution for prevention of central line-associated bloodstream infections. Antimicrob Agents Chemother, 60(9): 5175–5181.
22. Van Krevelen DW, Te Nijenhuis K. Properties of polymers: their correlation with chemical struc-ture; their numerical estimation and prediction from additive group contributions.4th ed. Neth-erlands: Elsevier; 2009.
23. Baghersad MH, Habibi A, Heydari A (2017). Synthesis, characterization, thermal and computational studies of novel tetra–azido compounds as energetic plasticiz-ers.
Journal of Molecular Structure, 1130:447-454.
24. Bézière N, Goossens L, Pommery J, et al (2008). New NSAIDs-NO hybrid mole-cules with antiproliferative properties on human prostatic cancer. Cell Lines. Bioorg Med Chem Lett, 18(16):4655-7.
25. Rosenblatt J, Reitzel RA, Raad I (2015). Caprylic acid and glyceryl trinitrate com-bination for eradication of biofilm. Anti-microb Agents Chemother, 59(3):1786-8.
26. Arastehfar A, Daneshnia F, Hafez A, et al (2020). Antifungal susceptibility, genotyp-ing, resistance mechanism, and clinical profile of Candida tropicalis blood isolates. Med Mycol J, 58:766–773
27. Spettel K, Barousch W, Makristathis A, et al (2019). Analysis of antifungal resistance genes in Candida albicans and Candida gla-brata using next generation sequencing. PLoS One, 14(1): e0210397.
28. Flowers SA, Colón B, Whaley SG, et al (2015). Contribution of clinically derived mutations in ERG11 to azole resistance in Candida albicans. Antimicrob Agents Chemother, 59(1):450-60.
29. Xiang M-J, Liu J-Y, Ni P-H, et al (2013). Erg11 mutations associated with azole re-sistance in clinical isolates of Candida albi-cans. FEMS Yeast Res, 13(4):386-93.
Files
IssueVol 50 No 9 (2021) QRcode
SectionOriginal Article(s)
Published2021-09-02
DOI https://doi.org/10.18502/ijph.v50i9.7060
Keywords
Nitroglycerin Candida albicans Antifungal activities

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Rashidi N, Rezaie S, Hashemi SJ, Habibi A, Baghersad MH, Daie R, Khodavaisy S, Bakhshi H, Salimi A, Getso MI, Rafat Z. Synthesis, Cytotoxicity Evaluation, and Antifungal Activity of Novel Nitroglycerin Derivatives against Clinical Candida albi-cans Isolates. Iran J Public Health. 2021;50(9):1872-1881.