Association of ADH1 and DDR48 Expression with Azole Resistance in Candida Albicans




Candida albicans, fluconazole resistance, CDR1, FLU1, ADH1, DDR48


Objectives: The ADH1 (alcohol dehydrogenase) and DDR48 genes were found to be upregulated in fluconazole resistant Candida albicans. Understanding the drug resistance mechanisms and genes will help in the development of new antifungal agents that can reverse drug resistance. This study aimed to investigate the role of ADH1and DDR48 genes in fluconazole resistance in C. albicans.

Methods: This study involved 19 fluconazole susceptible and 6 fluconazole resistant C. albicans isolates. The MICs of fluconazole were determined by the E-test. Quantitative expressions of ADH1, CDR1 (Candida Drug Resistance), DDR48 and FLU1 genes were assessed by real time PCR.

Results: There was a statistically significant higher expression levels of CDR1, FLU1, ADH1 and DDR48 in resistant and susceptible dose dependent isolates than in susceptible isolates (P = 0.009, 0.008, 0.01, 0.014 respectively). Strong positive correlations were observed between the expression levels of each of ADH1and DDR4 with azole resistance genes CDR1 and FLU1 [(rs) = 0.945, 0.815, respectively; P <0.001; (rs) = 0.852 and 0.76, respectively; P <0.001].

Conclusions: This is the first study that showed positive correlation between DDR48 and azole resistance genes. It indicated that ADH1 and DDR48 are associated with the resistance mechanisms of C. albicans to fluconazole. Identification of new drugs that target the proteins encoded by these genes will help in eradication of fluconazole resistant C. albicans.

Author Biographies

Marwa Salah Mostafa, Faculty of Medicine, Cairo University

Medical Microbiology and Immunology, Lecturer

Alaa Awad, Faculty of Medicine, Cairo University

Medical Microbiology and Immunology, Lecturer


Chen SC, O'Donnell ML, Gordon S, Gilbert GL. Antifungal susceptibility testing using the E-test: comparison with the broth macrodilution technique. J Antimicrob Chemother 1996; 37(2): 265-73.

Cleary IA, MacGregor NB, Saville SP, Thomas DP. Investigating the function of Ddr48p in Candida albicans. Eukaryot Cell 2012; 11(6): 718-24.

Dib L, Hayek P, Sadek H, Beyrouthy B, Khalaf RA. The Candida albicans Ddr48 protein is essential for filamentation, stress response, and confers partial antifungal drug resistance. Med Sci Monit 2008; 14(6): BR113-21.

Guo H, Zhang XL, Gao LQ, Li SX, Song YJ, Zhang H. Alcohol dehydrogenase I expression correlates with CDR1, CDR2 and FLU1 expression in Candida albicans from patients with vulvovaginal candidiasis, Chin Med J 2013; 126(11): 2098-102.

Lee MK, Williams LE, Warnock DW, Arthington-Skaggs BA. Drug resistance genes and trailing growth in Candida albicans isolates. J Antimicrob Chemother 2004; 53(2): 217-24.

Leskovac V, Trivić S, Pericin D. The three zinc-containing alcohol dehydrogenases from baker’s yeast, Saccharomyces cerevisiae. FEMS Yeast Res 2002; 2(4): 481-94.

Matar MJ, Ostrosky-Zeichner L, Paetznick VL, Rodriguez JR, Chen E, Rex JH. Correlation between E-test, disk diffusion, and microdilution methods for antifungal susceptibility testing of fluconazole and voriconazole. Antimicrob Agents Chemother 2003; 47(5): 1647-51.

Pfaller MA, Messer SA, Karlsson A, Bolmström A. Evaluation of the E-test method for determining fluconazole susceptibilities of 402 clinical yeast isolates by using three different agar media. J Clin Microbiol 1998; 36(9): 2586-9.

Rogers PD, Barker KS. Genome-wide expression profile analysis reveals coordinately regulated genes associated with stepwise acquisition of azole resistance in Candida albicans clinical isolates. Antimicrob Agents Chemother 2003; 47(4): 1220–7.

Siikala E, Bowyer P, Richardson M, Saxen H, Sanglard D, Rautemaa R. ADH1 expression inversely correlates with CDR1 and CDR2 in Candida albicans from chronic oral candidosis in APECED (APS-I) patients. FEMS Yeast Research 2011; 11(6): 494-8.

Tapia C, León E, Palavecino E. Antifungal susceptibility of yeasts by E-test. Comparison of 3 media. Rev Med Chil 2003; 131(3): 299-302.

Thomas DP, Pitarch A, Monteoliva L, Gil C, Lopez-Ribot JL. Proteomics to study Candida albicans biology and pathogenicity. Infect Disord Drug Targets 2006; 6(4): 335–41.

Torres DNA, Alvarez MCA, Rondón SMA. Fluconazole susceptibility of invasive Candida sp isolates as determined by three methods: Bogotá - Colombia. Rev Chilena Infectol 2009; 26(2): 135-43.

Treger JM, McEntee K. Structure of the DNA damage-inducible gene DDR48 and evidence for its role in mutagenesisin Saccharomycescerevisiae. Mol Cell Biol 1990; 10(6): 3174-84.

Vandenbossche I, Vaneechoutte M, Vandevenne M, De Baere T, Verschraegen G. Susceptibility testing of fluconazole by the NCCLS broth macrodilution method, E-test, and disk diffusion for application in the routine laboratory. J Clin Microbiol 2002; 40(3): 918-21.

Wang Z, Zhang G, Zhang X, Wu S, Yin X, Hong Zhang H. Proteomic analysis of fluconazole resistance in Candida albicans. Afr J Pharm Pharmaco 2012; 6(16): 1226-30.

Yan L, Zhang JD, Cao YB, Gao PH, Jiang YY. Proteomic analysis reveals a metabolism shift in a laboratory fluconazole-resistant Candida albicans strain. J Proteome Res 2007; 6: 2248- 56.