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Journal of Antimicrobial Chemotherapy (2009) 63, 337 – 339doi:10.1093/jac/dkn488Advance Access publication 26 November 2008 Curcumin as a promising antifungal of clinical interest C. V. B. Martins1,2, D. L. da Silva1, A. T. M. Neres3, T. F. F. Magalha˜es1, G. A. Watanabe1, 1Departamento de Microbiologia, ICB, UFMG, Av. Pres. Antonio Carlos, 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil; 2Centro de Engenharias e Cieˆncias Exatas, UNIOESTE, Rua da Faculdade, 645, Jardim La Salle, Toledo, PR 85903-000, Brazil; 3Grupo de Estudos em Quı´mica Orgaˆnica e Biolo´gica (GEQOB), Departamento de Quı´mica, ICEx, UFMG, Av. Pres. Antonio Carlos, 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil; 4Departamento de Botaˆnica, ICB, UFMG, Av. Pres. Antonio Carlos, 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil Received 19 August 2008; returned 21 October 2008; revised 28 October 2008; accepted 5 November 2008 Objectives: The antifungal activity of curcumin was evaluated against 23 fungi strains and its in vitroinhibitory effect on the adhesion of Candida species to human buccal epithelial cells (BEC) was also Methods: The antifungal susceptibility was evaluated by broth microdilution assay following the CLSI(formerly the NCCLS) guidelines. The inhibitory effect of curcumin on the cell adhesion was performedwith Candida species and BEC.
Results: Paracoccidioides brasiliensis isolates were the most susceptible to curcumin while thegrowth of Aspergillus isolates was not affected. Curcumin was much more efficient than fluconazole ininhibiting the adhesion of Candida species to BEC, particularly those strains isolated from the buccalmucosa of AIDS patients.
Conclusions: The lack of antifungal compounds with reduced side effects highlights the importance ofstudying natural products for this purpose. Curcumin was a more potent antifungal than fluconazoleagainst P. brasiliensis, the causal agent of the neglected disease paracoccidioidomycosis. Curcumindramatically inhibited the adhesion of Candida species isolated from AIDS patients to BEC, demon-strating that curcumin is a promising lead compound that warrants further investigation into its thera-peutical use in immunocompromised patients.
Keywords: antifungal activity, adhesion, MIC, natural products where antifungal activity was assessed by experiments donewith crude extracts of C. longa.
Fungal infections have increased significantly, contributing to This work focused on the evaluation of curcumin antifungal the cause of morbidity and mortality. The increase in antimicro- activity against 23 fungi strains of clinical interest as well as its bial resistance and populations of patients at some risk, in con- ability to inhibit the adhesion of Candida spp. to human buccal junction with the restricted number of commercially available antifungal drugs that still present many side effects, are thecause for this problem.1,2 These limitations emphasize the needto develop new and more effective antifungal agents. Natural products are attractive prototypes for this purpose due to theirbroad spectrum of biological activities.3 All chemicals used in this study were obtained from Sigma, unless Curcumin is a yellow – orange polyphenol compound pro- duced by the rhizome of Curcuma longa plants, which is widely Twenty-three fungi strains, which included Candida spp., used as a spice in Asian cooking. This compound has been Cryptococcus neoformans, Sporothrix schenckii, Paracoccidioides shown to possess a wide range of pharmacological activities,4 brasiliensis and Aspergillus spp., were the subject of this study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
*Corresponding author. Tel: þ55-31-3409-6373; Fax: þ55-31-3409-5700; E-mail: adefatima@qui.ufmg.br . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
# The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: journals.permissions@oxfordjournals.org Table 1. MICs of curcumin that completely inhibited the growth of The curcumin effect on P. brasiliensis 17 was roughly the same as that of fluconazole, while P. brasiliensis Pb01 and 608 strainswere more susceptible to fluconazole (Table 1).
Even though the greatest antifungal activity of curcumin was against P. brasiliensis isolates, promising results were alsoachieved for this compound against other fungi species. For instance, curcumin was twice as potent as fluconazole in thegrowth inhibition of the opportunistic yeast S. schenckii (Table 1). S. schenckii promotes infections of hosts with pre- disposing conditions, which includes alcoholics, diabetics, trans- plant recipients, and patients with haematological malignancies, chronic obstructive pulmonary disease, long-term treatment with Curcumin (32 mg/L) was able to inhibit the growth of C. neoformans and the clinical isolates of Candida dubliniensis Cd22 and Cd28. Non-albicans Candida species are emerging as colonizers and pathogens causing nosocomial fungal blood- stream infections.9 Candida albicans was the most susceptible to curcumin among the Candida species studied (Table 1). The growth of the remaining fungi isolates was only affected by cur- Curcumin was used to further explore its ability to prevent the adhesion of Candida species to BEC. These experiments were performed with curcumin at its MIC values. Curcumin was able to inhibit the adhesion to BEC of all the Candida species studied, being more potent than the commercial anti- fungal fluconazole (Figure 1a). C. dubliniensis Cd22 and Cd28 had the most significant reduction in adhesion to BEC (63% and 74%, respectively) in the presence of curcumin. The cur- cumin effect on all clinical isolates was 2.5 – 6.0-fold higher than that of fluconazole. Figure 1(b – d) shows the representa- tive images of C. dubliniensis Cd28 adhesion to BEC. These strains were isolated from the oral cavities of AIDS patients at the Santa Maria University Hospital, RS, Brazil. Other C.
dubliniensis strains were reported to be recovered from (Table 1). Dimorphic fungi (S. schenckii and P. brasiliensis) were HIV-infected and AIDS patients under fluconazole treatment for oropharyngeal candidiasis, suggesting that this commercial Analysis of in vitro susceptibility was performed by broth micro- antifungal was either selecting resistant Candida isolates or dilution assay following the CLSI (formerly the NCCLS) guidelines inducing cell adhesion.10 The adhesion of microorganisms to for yeasts and filamentous fungi.5,6 Curcumin was tested in the host mucosal surfaces is a prerequisite for colonization and range of 0.5 – 256 mg/L and fluconazole (0.06 – 64 mg/L; Pfizer, Sa˜o infection.7 Our results indicate that curcumin is a promising Paulo, Brazil) was included as a positive control. The MIC values lead compound for the design of new antifungal agents correspond to the lowest concentrations that did not allow for the capable of inhibiting the adhesion of C. dubliniensis. The detection of any visual fungal growth.
The adhesion assay was carried out according to Lyon and de adhesion of Candida tropicalis to BEC was inhibited by 55% Resende.7 Briefly, Candida spp. isolates were exposed to curcumin in the presence of curcumin while the inhibition caused by flu- at its MIC value for 1 h, and were then incubated with BEC for conazole accounted for only 13%. Curcumin was 2.5-fold another 1 h. Assay with Candida parapsilosis was carried out with more potent than fluconazole at inhibiting the adhesion of 256 mg/L curcumin since its MIC value was not determined. The C. albicans or C. parapsilosis to BEC (Figure 1a).
number of yeast cells that adhered to BEC was quantified by light To the best of our knowledge, this study reports for the microscopy (Â400 magnification) from 50 randomly chosen BEC.
first time the effect of curcumin on the growth and celladhesion to BEC of fungi of clinical interest. Our in vitroresults highlight the potential of curcumin as an effective anti- fungal against different P. brasiliensis strains, being muchmore potent than the commercial antifungal fluconazole. This The MICs of curcumin that completely abolished the growth of natural product was also much more efficient than fluconazole fungi strains are shown in Table 1. P. brasiliensis isolates were in inhibiting the adhesion of Candida species to BEC, particu- the most susceptible to curcumin. Curcumin was 32-fold more larly those strains isolated from the buccal mucosa of AIDS potent than fluconazole in the inhibition of P. brasiliensis MG05 growth. Fluconazole was also 4-fold less potent than curcumin Synthesis of curcumin analogues and evaluation of their anti- in inhibiting the growth of P. brasiliensis Pb18 and B339.
fungal activities are in progress in our laboratory.
Figure 1. Effect of curcumin on the adhesion of Candida species to BEC. Percentage of cell adhesion inhibition (a). The results obtained with curcuminwere significantly different from those obtained with fluconazole (P , 0.008; Kruskal– Wallis test). Micrography of BEC in the presence of untreated C.
dubliniensis Cd28 (b), C. dubliniensis Cd28 pre-treated with 0.5 mg/L fluconazole (c) and C. dubliniensis Cd28 pre-treated with 32 mg/L curcumin (d).
Arrows indicate fungal adhesion. (b), (c) and (d) correspond to images of cells at Â400 magnification.
4. Chattopadhyay I, Biswas K, Bandyopadhyay U et al. Turmeric and curcumin: biological actions and medicinal applications. Curr Sci We thank Dr Sydney Alves (Hospital Universita´rio Santa Maria, RS, Brazil) for kindly providing the isolates of C. dubliniensis.
Reference Method for Broth Dilution Antifungal Susceptibility Testing ofYeast—Second Edition: Approved Standard M27-A2. (Formerly the This work was funded by FAPEMIG, CNPq and CAPES.
Reference Method for Broth Dilution Antifungal Susceptibility Testing ofFilamentous Fungi: Approved Standard M38-A. (Formerly the NCCLS)Wayne, PA, USA, 2002.
7. Lyon JP, de Resende MA. Correlation between adhesion, enzyme production, and susceptibility to fluconazole in Candida albi- cans obtained from denture wearers. Oral Surg Oral Med Oral PatholOral Radiol Endod 2006; 102: 632 – 8.
8. Al-Tawfiq JA, Wools KK. Disseminated sporotrichosis and human immunodeficiency virus infection. Clin Infect Dis 1998; 26: 1. Ghannoum MA, Rice LB. Antifungal agents: mode of action, mechanism of resistance, and correlation of these mechanisms with 9. Krcmery V, Barnes AJ. Non-albicans Candida spp. causing fun- bacterial resistance. Clin Microbiol Rev 1999; 12: 501 – 17.
gaemia: pathogenicity and antifungal resistance. J Hosp Infect 2002; 2. Nucci M, Marr KA. Emerging fungal diseases. Clin Infect Dis 10. Zepelin MBV, Niederhaus T, Gross U et al. Adherence of differ- 3. Newman DJ, Cragg CM. Natural products as sources of new ent Candida dubliniensis isolates in the presence of fluconazole. AIDS drugs over the last 25 years. J Nat Prod 2007; 70: 461 – 77.

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