Skip to main content
Top
Published in: Odontology 2/2022

01-04-2022 | Candida Balanitis | Original Article

Synergistic effect of thymoquinone and nystatin in the treatment of oral candidiasis; an in vitro study

Authors: Özge Özdal Zincir, Umut Özdal, Özge Ünlü, Mehmet Demirci, Ahmet Bülent Katiboğlu, Edibe Egil, Gülay Altan Şallı

Published in: Odontology | Issue 2/2022

Login to get access

Abstract

The effectiveness of antifungal agents may be insufficient against resistant strains in some cases of oral candidiasis. The aim of this study was to evaluate the antifungal effect of thymoquinone against Candida albicans, Candida tropicalis, Candida glabrata and Candida krusei strains and the synergistic antifungal activity of these strains in combination with nystatin. To evaluate in vitro antifungal activity and interactions between thymoquinone and nystatin, substances were tested against Candida albicans ATCC 10,231, C. tropicalis ATCC 750, C.krusei ATCC 6258 and C. glabrata ATCC 2001 standard strains both individually and combinationally via microdilution method. MIC and ΣFIC index value were analysed. The Kruskal Wallis test and Bonferroni test were used for statistical evaluations. Statistical significance was set at p < 0.05. A statistically significant difference was observed between the mean ranks of all Candida species and doses of thymoquinone, nystatin, and the combination thymoquinone-nystatin (p < 0.05). MIC values for thymoquinone were determined as 15 μg/mL for C. albicans, C. tropicalis and C. krusei while it was 30 μg/mL for C. glabrata. Moreover, MIC for nystatin was found as 1.875 μg/mL for C. albicans, C. tropicalis and C. krusei, whereas it was 7.5 μg/mL in C. glabrata. Interaction assays and ΣFIC index value revealed that, TQ and nystatin have a synergistic effect against to all strains. Thymoquinone was found to have antifungal activity on Candida species and synergistic effect when combined with nystatin.
Literature
1.
go back to reference Coutinho HDM. Factors influencing the virulence of Candida Spp. W Indian Med J. 2009;58(2):160–3.PubMed Coutinho HDM. Factors influencing the virulence of Candida Spp. W Indian Med J. 2009;58(2):160–3.PubMed
2.
go back to reference de Castro RD, de Souza TM, Bezerra LM, Ferreira GL, Costa EM, Cavalcanti AL. Antifungal activity and mode of action of thymol and its synergism with nystatin against Candida species involved with infections in the oral cavity: an in vitro study. BMC Complement Altern Med. 2015;15:417.CrossRef de Castro RD, de Souza TM, Bezerra LM, Ferreira GL, Costa EM, Cavalcanti AL. Antifungal activity and mode of action of thymol and its synergism with nystatin against Candida species involved with infections in the oral cavity: an in vitro study. BMC Complement Altern Med. 2015;15:417.CrossRef
3.
go back to reference Mangueira DFB, Mangueira LFB, Diniz MFFM. Candidose oral. R bras ci Saúde. 2010;14(2):69–72.CrossRef Mangueira DFB, Mangueira LFB, Diniz MFFM. Candidose oral. R bras ci Saúde. 2010;14(2):69–72.CrossRef
4.
go back to reference Capistrano HM, Assis EM, Leal RM, Alvarez-Leite ME, Brener S, Bastos EM. Brazilian Green própolis compared to miconazole gel in the treatment of Candida-associated denture stomatitis. Evid Based Complement Alternat Med. 2013;2013:947980.CrossRef Capistrano HM, Assis EM, Leal RM, Alvarez-Leite ME, Brener S, Bastos EM. Brazilian Green própolis compared to miconazole gel in the treatment of Candida-associated denture stomatitis. Evid Based Complement Alternat Med. 2013;2013:947980.CrossRef
5.
go back to reference Bondaryk M, Kurzatkowski W, Staniszewska M. Antifungal agents commonly used in the superficial and mucosal candidiasis treatment: mode of action and resistance development. Postępy Dermatol Alergol. 2013;30(5):293–301.CrossRef Bondaryk M, Kurzatkowski W, Staniszewska M. Antifungal agents commonly used in the superficial and mucosal candidiasis treatment: mode of action and resistance development. Postępy Dermatol Alergol. 2013;30(5):293–301.CrossRef
6.
go back to reference Kamikawa Y, Mori Y, Nagayama T, Fujisaki J, Hirabayashi D, Sakamoto R, et al. Frequency of clinically isolated strains of oral Candida species at Kagoshima University Hospital, Japan, and their susceptibility to antifungal drugs in 2006–2007 and 2012–2013. BMC Oral Health. 2014;14:14.CrossRef Kamikawa Y, Mori Y, Nagayama T, Fujisaki J, Hirabayashi D, Sakamoto R, et al. Frequency of clinically isolated strains of oral Candida species at Kagoshima University Hospital, Japan, and their susceptibility to antifungal drugs in 2006–2007 and 2012–2013. BMC Oral Health. 2014;14:14.CrossRef
7.
go back to reference Freires IA, Furletti VF, Sartoratto A, Alencar SM, Figueira GM, Murata RM, et al. Coriandrum sativum L. (coriander) essential oil: antifungal activity and mode of action on Candida spp., and molecular targets affected in human whole-genome expression. PLoS ONE. 2014;9(6):e99086.CrossRef Freires IA, Furletti VF, Sartoratto A, Alencar SM, Figueira GM, Murata RM, et al. Coriandrum sativum L. (coriander) essential oil: antifungal activity and mode of action on Candida spp., and molecular targets affected in human whole-genome expression. PLoS ONE. 2014;9(6):e99086.CrossRef
8.
go back to reference Wong SSW, Samaranayake LP, Seneviratne CJ. In pursuit of the ideal antifungal agent for Candida infections: high-throughput screening of small molecules. Drug Discov Today. 2014;19(11):1721–30.CrossRef Wong SSW, Samaranayake LP, Seneviratne CJ. In pursuit of the ideal antifungal agent for Candida infections: high-throughput screening of small molecules. Drug Discov Today. 2014;19(11):1721–30.CrossRef
9.
go back to reference Samaranayake LP, Keung Leung W, Jin L. Oral mucosal fungal infections. Periodontol. 2000;2009(49):39–59. Samaranayake LP, Keung Leung W, Jin L. Oral mucosal fungal infections. Periodontol. 2000;2009(49):39–59.
10.
go back to reference Sklenar Z, Scigel V, Horackova K, Slanar O. Compounded preparations with nystatin for oral and oromucosal administration. Acta Pol Pharm. 2013;70(4):759–62.PubMed Sklenar Z, Scigel V, Horackova K, Slanar O. Compounded preparations with nystatin for oral and oromucosal administration. Acta Pol Pharm. 2013;70(4):759–62.PubMed
11.
go back to reference Gotzsche PC, Johansen HK. Nystatin prophylaxis and treatment in severely immunodepressed patients. Cochrane Database Syst Rev. 2002;4:CD002033. Gotzsche PC, Johansen HK. Nystatin prophylaxis and treatment in severely immunodepressed patients. Cochrane Database Syst Rev. 2002;4:CD002033.
12.
go back to reference Jabalameli Z, Sabzghabaee A, Mohaghegh M, Maherolnaghsh M, Safavizadeh H, Dehghan P. Antifungal susceptibility of candida species ısolated from cancer patients with oral lesions undergoing chemotherapy. Int J Infect. 2017;4:e14178.CrossRef Jabalameli Z, Sabzghabaee A, Mohaghegh M, Maherolnaghsh M, Safavizadeh H, Dehghan P. Antifungal susceptibility of candida species ısolated from cancer patients with oral lesions undergoing chemotherapy. Int J Infect. 2017;4:e14178.CrossRef
13.
go back to reference Forouzanfar F, Bazzaz BS, Hosseinzadeh H. Black cumin (Nigella sativa) and its constituent (thymoquinone): a review on antimicrobial effects. Iran J Basic Med Sci. 2014;17(12):929–38.PubMedPubMedCentral Forouzanfar F, Bazzaz BS, Hosseinzadeh H. Black cumin (Nigella sativa) and its constituent (thymoquinone): a review on antimicrobial effects. Iran J Basic Med Sci. 2014;17(12):929–38.PubMedPubMedCentral
14.
go back to reference Shafiq H, Ahmad A, Masud T, Kalem M. Cardio-protective and anti-cancer therapeutic potential of Nigella sativa. Iran J Basic Med Sci. 2014;17(12):967–79.PubMedPubMedCentral Shafiq H, Ahmad A, Masud T, Kalem M. Cardio-protective and anti-cancer therapeutic potential of Nigella sativa. Iran J Basic Med Sci. 2014;17(12):967–79.PubMedPubMedCentral
15.
go back to reference Darakhshan S, Bidmeshki Pour A, Hosseinzadeh Colagar A, Sisakhtnezhad S. Thymoquinone and its therapeutic potentials. Pharmacol Res. 2015;95–96:138–58.CrossRef Darakhshan S, Bidmeshki Pour A, Hosseinzadeh Colagar A, Sisakhtnezhad S. Thymoquinone and its therapeutic potentials. Pharmacol Res. 2015;95–96:138–58.CrossRef
16.
go back to reference Kara MI, Erciyas K, Altan AB, Ozkut M, Ay S, Inan S. Thymoquinone accelerates new bone formation in the rapid maxillary expansion procedure. Arch Oral Biol. 2012;57(4):357–63.CrossRef Kara MI, Erciyas K, Altan AB, Ozkut M, Ay S, Inan S. Thymoquinone accelerates new bone formation in the rapid maxillary expansion procedure. Arch Oral Biol. 2012;57(4):357–63.CrossRef
17.
go back to reference Mahmoudvand H, Sepahvand A, Jahanbakhsh S, Ezatpour B, Ayatollahi Mousavi SA. Evaluation of antifungal activities of the essential oil and various extracts of Nigella sativa and its main component, thymoquinone against pathogenic dermatophyte strains. J Mycol Med. 2014;24(4):e155–61.CrossRef Mahmoudvand H, Sepahvand A, Jahanbakhsh S, Ezatpour B, Ayatollahi Mousavi SA. Evaluation of antifungal activities of the essential oil and various extracts of Nigella sativa and its main component, thymoquinone against pathogenic dermatophyte strains. J Mycol Med. 2014;24(4):e155–61.CrossRef
18.
go back to reference Botelho MG. Fractional inhibitory concentration index of combinations of antibacterial agents against cariogenic organisms. J Dent. 2000;28(8):565–70.CrossRef Botelho MG. Fractional inhibitory concentration index of combinations of antibacterial agents against cariogenic organisms. J Dent. 2000;28(8):565–70.CrossRef
19.
go back to reference Jenkinson HF, Lamont RJ. Oral microbial communities in sickness and in health. Trends Microbiol. 2005;13(12):589–95.CrossRef Jenkinson HF, Lamont RJ. Oral microbial communities in sickness and in health. Trends Microbiol. 2005;13(12):589–95.CrossRef
20.
go back to reference Avila M, Ojcius DM, Yilmaz O. The oral microbiota: living with a permanent guest. DNA Cell Biol. 2009;28(8):405–11.CrossRef Avila M, Ojcius DM, Yilmaz O. The oral microbiota: living with a permanent guest. DNA Cell Biol. 2009;28(8):405–11.CrossRef
21.
go back to reference Aas JA, Barbuto SM, Alpagot T, Olsen I, Dewhirst FE, Paster BJ. Subgingival plaque microbiota in HIV positive patients. J Clin Periodontol. 2007;34(3):189–95.CrossRef Aas JA, Barbuto SM, Alpagot T, Olsen I, Dewhirst FE, Paster BJ. Subgingival plaque microbiota in HIV positive patients. J Clin Periodontol. 2007;34(3):189–95.CrossRef
22.
23.
go back to reference Dangi YS, Soni ML, Namdeo KP. Oral candidiasis: a review. Int J Pharm Pharm Sci. 2010;2(4):36–41. Dangi YS, Soni ML, Namdeo KP. Oral candidiasis: a review. Int J Pharm Pharm Sci. 2010;2(4):36–41.
24.
go back to reference Pfaller M, Neofytos D, Diekema D, Azie N, Meier-Kriesche HU, Quan SP, et al. Epidemiology and outcomes of candidemia in 3648 patients: data from the prospective antifungal therapy (PATH Alliance®) registry, 2004–2008. Diagn Microbiol Infect Dis. 2012;74(4):323–31.CrossRef Pfaller M, Neofytos D, Diekema D, Azie N, Meier-Kriesche HU, Quan SP, et al. Epidemiology and outcomes of candidemia in 3648 patients: data from the prospective antifungal therapy (PATH Alliance®) registry, 2004–2008. Diagn Microbiol Infect Dis. 2012;74(4):323–31.CrossRef
25.
go back to reference Epstein JB, Polsky B. Oropharyngeal candidiasis: a review of its clinical spectrum and current therapies. Clin Ther. 1998;20(1):40–57.CrossRef Epstein JB, Polsky B. Oropharyngeal candidiasis: a review of its clinical spectrum and current therapies. Clin Ther. 1998;20(1):40–57.CrossRef
26.
27.
go back to reference Pappas PG, Kauffman CA, Andes D, Benjamin DK, Calandra TF, Edwards JE, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(5):503–35.CrossRef Pappas PG, Kauffman CA, Andes D, Benjamin DK, Calandra TF, Edwards JE, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(5):503–35.CrossRef
28.
go back to reference WHO Guidelines Approved by the Guidelines Review Committee. Guidelines on the Treatment of Skin and Oral HIV-Associated Conditions in Children and Adults. Geneva: World Health Organization. Copyright (c) World Health Organization 2014; 2014. WHO Guidelines Approved by the Guidelines Review Committee. Guidelines on the Treatment of Skin and Oral HIV-Associated Conditions in Children and Adults. Geneva: World Health Organization. Copyright (c) World Health Organization 2014; 2014.
29.
go back to reference Kundu J, Kim DH, Kundu JK, Chun KS. Thymoquinone induces heme oxygenase-1 expression in HaCaT cells via Nrf2/ARE activation: Akt and AMPKalpha as upstream targets. Food Chem Toxicol. 2014;65:18–26.CrossRef Kundu J, Kim DH, Kundu JK, Chun KS. Thymoquinone induces heme oxygenase-1 expression in HaCaT cells via Nrf2/ARE activation: Akt and AMPKalpha as upstream targets. Food Chem Toxicol. 2014;65:18–26.CrossRef
30.
go back to reference Alhebshi AH, Gotoh M, Suzuki I. Thymoquinone protects cultured rat primary neurons against amyloid beta-induced neurotoxicity. Biochem Biophys Res Commun. 2013;433(4):362–7.CrossRef Alhebshi AH, Gotoh M, Suzuki I. Thymoquinone protects cultured rat primary neurons against amyloid beta-induced neurotoxicity. Biochem Biophys Res Commun. 2013;433(4):362–7.CrossRef
31.
go back to reference Al-Bayaty F, Kamaruddin A, Ismail M, Abdulla M. Formulation and evaluation of a new biodegradable periodontal chip containing thymoquinone in a chitosan base for the management of chronic periodontitis. J Nanomater. 2013;3:397308. Al-Bayaty F, Kamaruddin A, Ismail M, Abdulla M. Formulation and evaluation of a new biodegradable periodontal chip containing thymoquinone in a chitosan base for the management of chronic periodontitis. J Nanomater. 2013;3:397308.
32.
go back to reference Gholamnezhad Z, Havakhah S, Boskabady MH. Preclinical and clinical effects of Nigella sativa and its constituent, thymoquinone: a review. J Ethnopharmacol. 2016;190:372–86.CrossRef Gholamnezhad Z, Havakhah S, Boskabady MH. Preclinical and clinical effects of Nigella sativa and its constituent, thymoquinone: a review. J Ethnopharmacol. 2016;190:372–86.CrossRef
34.
go back to reference Omar OM, Khattab NM, Khater DS. Nigella sativa oil as a pulp medicament for pulpotomized teeth: a histopathological evaluation. J Clin Pediatr Dent. 2012;36(4):335–42.CrossRef Omar OM, Khattab NM, Khater DS. Nigella sativa oil as a pulp medicament for pulpotomized teeth: a histopathological evaluation. J Clin Pediatr Dent. 2012;36(4):335–42.CrossRef
35.
go back to reference Piras A, Rosa A, Marongiu B, Porcedda S, Falconieri D, Dessì MA, et al. Chemical composition and in vitro bioactivity of the volatile and fixed oils of Nigella sativa L. extracted by supercritical carbon dioxide. Ind Crops Prod. 2013;46:317–23.CrossRef Piras A, Rosa A, Marongiu B, Porcedda S, Falconieri D, Dessì MA, et al. Chemical composition and in vitro bioactivity of the volatile and fixed oils of Nigella sativa L. extracted by supercritical carbon dioxide. Ind Crops Prod. 2013;46:317–23.CrossRef
36.
go back to reference Khan MA, Aljarbou AN, Khan A, Younus H. Liposomal thymoquinone effectively combats fluconazole-resistant Candida albicans in a murine model. Int J Biol Macromol. 2015;76:203–8.CrossRef Khan MA, Aljarbou AN, Khan A, Younus H. Liposomal thymoquinone effectively combats fluconazole-resistant Candida albicans in a murine model. Int J Biol Macromol. 2015;76:203–8.CrossRef
37.
go back to reference Johnson MD, Macdougall C, Ostrosky-Zeichner L, Perfect JR, Rex JH. Combination antifungal therapy. J Antimicrob Chemother. 2004;48(3):693–715.CrossRef Johnson MD, Macdougall C, Ostrosky-Zeichner L, Perfect JR, Rex JH. Combination antifungal therapy. J Antimicrob Chemother. 2004;48(3):693–715.CrossRef
38.
go back to reference Ning Y, Ling J, Wu CD. Synergistic effects of tea catechin epigallocatechin gallate and antimycotics against oral Candida species. Arch Oral Biol. 2015;60(10):1565–70.CrossRef Ning Y, Ling J, Wu CD. Synergistic effects of tea catechin epigallocatechin gallate and antimycotics against oral Candida species. Arch Oral Biol. 2015;60(10):1565–70.CrossRef
39.
go back to reference Lu M, Li T, Wan J, Li X, Yuan L, Sun S. Antifungal effects of phytocompounds on Candida species alone and in combination with fluconazole. Int J Antimicrob Agents. 2017;49(2):125–36.CrossRef Lu M, Li T, Wan J, Li X, Yuan L, Sun S. Antifungal effects of phytocompounds on Candida species alone and in combination with fluconazole. Int J Antimicrob Agents. 2017;49(2):125–36.CrossRef
Metadata
Title
Synergistic effect of thymoquinone and nystatin in the treatment of oral candidiasis; an in vitro study
Authors
Özge Özdal Zincir
Umut Özdal
Özge Ünlü
Mehmet Demirci
Ahmet Bülent Katiboğlu
Edibe Egil
Gülay Altan Şallı
Publication date
01-04-2022
Publisher
Springer Singapore
Published in
Odontology / Issue 2/2022
Print ISSN: 1618-1247
Electronic ISSN: 1618-1255
DOI
https://doi.org/10.1007/s10266-021-00667-4

Other articles of this Issue 2/2022

Odontology 2/2022 Go to the issue