Fluconazole and amphotericin-B resistance are associated with increased
catalase and superoxide dismutase activity in <i>Candida albicans</i> and <i>Candida
dubliniensis</i>

Linares, Carlos Eduardo Blanco; Giacomelli, Sandro Rogério; Altenhofen, Delsi; Alves, Sydney Hartz; Morsch, Vera Maria; Schetinger, Maria Rosa Chitolina

doi:10.1590/0037-8682-0190-2013

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Major Articles • Rev. Soc. Bras. Med. Trop. 46 (6) • Nov-Dec 2013 • https://doi.org/10.1590/0037-8682-0190-2013 copy

Fluconazole and amphotericin-B resistance are associated with increased catalase and superoxide dismutase activity in Candida albicans and Candida dubliniensis

Authorship SCIMAGO INSTITUTIONS RANKINGS

Introduction

Candida dubliniensis, a new species of Candida that has been recovered from several sites in healthy people, has been associated with recurrent episodes of oral candidiasis in AIDS and HIV-positive patients. This species is closely related to C. albicans. The enzymatic activity of C. dubliniensis in response to oxidative stress is of interest for the development of drugs to combat C. dubliniensis.

Methods

Fluconazole- and amphotericin B-resistant strains were generated as described by Fekete-Forgács et al. (2000). Superoxide dismutase (SOD) and catalase assays were performed as described by McCord and Fridovich (1969) and Aebi (1984), respectively.

Results

We demonstrated that superoxide dismutase (SOD) and catalase activities were significantly higher (p<0.05) in the fluconazole- and amphotericin B-resistant strains of C. dubliniensis and C. albicans than in the sensitive strains. The catalase and SOD activities were also significantly (p<0.01) higher in the sensitive and resistant C. albicans strains than in the respective C. dubliniensis strains.

Conclusions

These data suggest that C. albicans is better protected from oxidative stress than C. dubliniensis and that fluconazole, like amphotericin B, can induce oxidative stress in Candida; oxidative stress induces an adaptive response that results in a coordinated increase in catalase and SOD activities.

Catalase; Superoxide dismutase; Candida albicans ; Candida dubliniensis

Strains	Mean SOD activity [U mg protein^–1]		Mean catalase activity [ΔE min^–1 (mg protein)^–1]
Strains	sensitive^a a Fluconazole-sensitive C. dubliniensis;	resistant^b b Fluconazole-resistant C. dubliniensis (64µg/ml–1); ,^c c Statistical analyses revealed significant differences between the SOD activities of the fluconazole-resistant and fluconazole-sensitive C. dubliniensis groups (p < 0.01);	sensitive^a a Fluconazole-sensitive C. dubliniensis;	resistant^b b Fluconazole-resistant C. dubliniensis (64µg/ml–1); ,^d d Statistical analyses revealed significant differences between the catalase activities of the fluconazole-resistant and fluconazole-sensitive C. dubliniensis groups (p < 0.01).
01	13.4 ± 6.0	48.8 ± 2.8	0.5 ± 0.2	1.6 ± 0.1
02	56.4 ± 17.7	113.6 ± 23.6	1.9 ± 0.4	3.7 ± 0.1
03	27.1 ± 3.6	21.9 ± 5.2	0.8 ± 0.2	1.1 ± 0.1
04	5.1 ± 2.9	10.3 ± 2.5	0.5 ± 0.1	0.6 ± 0.1
05	17.2 ± 11.8	130.2 ± 33.7	1.5 ± 0.3	3.4 ± 0.5
07	14.0 ± 2.2	17.7 ± 3	1.1 ± 0.05	1.7 ± 0.4
09	28.2 ± 2.9	38.8 ± 12.2	0.6 ± 0.05	0.9 ± 0.2
11	7.4 ± 1.2	47.2 ± 6.1	1.9 ± 0.6	1.6 ± 0.7
13	83.2 ± 5.8	67.9 ± 6.2	1.5 ± 0.4	1.7 ± 0.7

Strains	Mean SOD activity [U mg protein^–1]		Mean catalase activity [ΔE min^–1 (mg protein)^–1]
Strains	sensitive^a a Amphotericin B-sensitive C. dubliniensis;	resistant^b b C. dubliniensis resistant to 2µg/ml–1 amphotericin B; ,^c c Statistical analyses indicated significant differences between the SOD activities of the C. dubliniensis cells resistant to 2µg/ml–1 amphotericin B and the sensitive C. dubliniensis cells (p < 0.01).	sensitive^a a Amphotericin B-sensitive C. dubliniensis;	resistant^b b C. dubliniensis resistant to 2µg/ml–1 amphotericin B; ,^d d Statistical analyses indicated significant differences between the catalase activities of the C. dubliniensis cells resistant to 2µg/ml–1 amphotericin B and the sensitive C. dubliniensis cells (p < 0.01).
01	15.5 ± 0.4	69.7 ± 20.7	0.6 ± 0.1	2.4 ± 0.5
02	15 ± 1.5	22.6 ± 3.0	0.8 ± 0.1	0.9 ± 0.1
03	13.5. ± 0.4	37.8 ± 6.8	0.9 ± 0.01	2.1 ± 0.1
04	27.2 ± 1.8	50.7 ± 5.0	1.1 ± 0.1	1.8 ± 0.01
05	22.1 ± 3.2	37.3 ± 3.5	1.0 ± 0.1	1.8 ± 0.2
07	15.7 ± 1.9	44.1 ± 13.3	1.1 ± 0.01	3.1 ± 0.01
09	47.2 ± 12.6	101.1 ± 24.1	1.6 ± 0.2	2.2 ± 0.3
11	57.9 ± 33.2	69.3 ± 4.7	1.7 ± 0.2	3.6 ± 0.6
13	35.5 ± 10.2	57.8 ± 8.1	0.8 ± 0.1	1.0 ± 0.1

Strains	Mean SOD activity [U mg protein^–1]		Mean catalase activity [ΔE min^–1 (mg protein)^–1]
Strains	sensitive^a a Fluconazole-sensitive C. albicans;	resistant^b b Fluconazole-resistant C. albicans (64µg/ml–1); ,^c c Statistical analyses revealed significant differences between the SOD activities of the fluconazole-resistant and fluconazole-sensitive C. albicans groups (p < 0.01);	sensitive^a a Fluconazole-sensitive C. albicans;	resistant^b b Fluconazole-resistant C. albicans (64µg/ml–1); ,^d d Statistical analyses revealed significant differences between the catalase activities of the fluconazole-resistant and fluconazole-sensitive C. albicans groups (p < 0.01).
Ca 10	177.4 ± 22.1	300.5 ± 2	2.8 ± 0.2	3.5 ± 0.6
Ca 81	230.4 ± 5.1	273.1 ± 2.8	2.2 ± 0.1	2.3 ± 0.4
Ca 119	269.6 ± 5.9	289.7 ± 21.3	1.5 ± 0.2	2.6 ± 0.3
Ca 170	139.2 ± 6.2	238.3 ± 16.9	1.6 ± 0.4	4.1 ± 0.2
Ca ATCC 44373	188 ± 2.5	205.3 ± 7	2.3 ± 0.2	3.8 ± 0.9

Strains	Mean SOD activity [U mg protein^–1]		Mean catalase activity [ΔE min^–1 (mg protein)^–1]
Strains	sensitive^a a Amphotericin B-sensitive C. albicans;	resistant^b b C. albicans resistant to 2 µg ml–1 amphotericin B; ,^c b C. albicans resistant to 2 µg ml–1 amphotericin B;	sensitive^a a Amphotericin B-sensitive C. albicans;	resistant^b b C. albicans resistant to 2 µg ml–1 amphotericin B; ,^d d Statistical analyses revealed differences between the catalase activities of the C. albicans cells resistant to 2µg/ml–1 amphotericin B and the sensitive C. albicans cells (p < 0.05).
Ca 10	22.1 ± 8.5	178.4 ± 15	3.1 ± 0.3	4.4 ± 0.3
Ca 81	116.2 ± 6.4	93 ± 4.8	2 ± 0.2	2.9 ± 0.3
Ca 119	106.6 ± 11.7	298.2 ± 21.3	1.5 ± 0.2	2.9 ± 0.8
Ca 170	186.1 ± 3.2	195 ± 6.9	1.3 ± 0.4	3.9 ± 0.1
Ca ATCC 44373	82.4 ± 4	269.3 ± 10.1	2.8 ± 0.1	4.8 ± 1.1

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[1] Address to: Dr. Carlos Eduardo Blanco Linares. Dept° Ciências da Saúde/URI. Av. Assis Brasil, 98400-000 Frederico Westphalen, RS, Brasil. Fax: 55 55 3744-9265. e-mail: clinares@terra.com.br