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Expression Patterns of ABC Transporter Genes in Fluconazole-Resistant Candida glabrata

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Abstract

Clinical management of fungal diseases is compromised by the emergence of antifungal drug resistance in fungi, which leads to elimination of available drug classes as treatment options. An understanding of antifungal resistance at molecular level is, therefore, essential for the development of strategies to combat the resistance. This study presents the assessment of molecular mechanisms associated with fluconazole resistance in clinical Candida glabrata isolates originated from Iran. Taking seven distinct fluconazole-resistant C. glabrata isolates, real-time PCRs were performed to evaluate the alternations in the regulation of the genes involved in drug efflux including CgCDR1, CgCDR2, CgSNQ2, and CgERG11. Gain-of-function (GOF) mutations in CgPDR1 alleles were determined by DNA sequencing. Cross-resistance to fluconazole, itraconazole, and voriconazole was observed in 2.5 % of the isolates. In the present study, six amino acid substitutions were identified in CgPdr1, among which W297R, T588A, and F575L were previously reported, whereas D243N, H576Y, and P915R are novel. CgCDR1 overexpression was observed in 57.1 % of resistant isolates. However, CgCDR2 was not co-expressed with CgCDR1. CgSNQ2 was upregulated in 71.4 % of the cases. CgERG11 overexpression does not seem to be associated with azole resistance, except for isolates that exhibited azole cross-resistance. The pattern of efflux pump gene upregulation was associated with GOF mutations observed in CgPDR1. These results showed that drug efflux mediated by adenosine-5-triphosphate (ATP)-binding cassette transporters, especially CgSNQ2 and CgCDR1, is the predominant mechanism of fluconazole resistance in Iranian isolates of C. glabrata. Since some novel GOF mutations were found here, this study also calls for research aimed at investigating other new GOF mutations to reveal the comprehensive understanding about efflux-mediated resistance to azole antifungal agents.

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Acknowledgements

This research was financially supported by Mazandaran University of Medical Sciences (Sari, Iran) [Grant No. 684].

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Authors and Affiliations

  1. Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran

    Atefeh Abdollahi Gohar, Mojtaba Nabili & Nasrin Amirrajab

  2. Invasive Fungi Research Centre, Mazandaran University of Medical Sciences, Sari, Iran

    Hamid Badali, Tahereh Shokohi & Maryam Moazeni

  3. Department of Medical Mycology and Parasitology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

    Hamid Badali, Tahereh Shokohi & Maryam Moazeni

  4. Iranian Social Security Organization, Mazandaran, Iran

    Mojtaba Nabili

  5. Department of Laboratory Sciences, School of Paramedicine/Infectious and Tropical Diseases Research Centre, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Nasrin Amirrajab

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  1. Atefeh Abdollahi Gohar
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Correspondence to Maryam Moazeni.

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Gohar, A.A., Badali, H., Shokohi, T. et al. Expression Patterns of ABC Transporter Genes in Fluconazole-Resistant Candida glabrata . Mycopathologia 182, 273–284 (2017). https://doi.org/10.1007/s11046-016-0074-8

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  • DOI: https://doi.org/10.1007/s11046-016-0074-8

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