Abstract
For years, antifungal drug resistance in Candida species has been associated to the expression of ATP-Binding Cassette (ABC) multidrug transporters. More recently, a few drug efflux pumps from the Drug:H+ Antiporter (DHA) family have also been shown to play a role in this process, although to date only the Candida albicans Mdr1 transporter has been demonstrated to be relevant in the clinical acquisition of antifungal drug resistance. This work provides evidence to suggest the involvement of the C. glabrata DHA transporters CgAqr1, CgQdr2, CgTpo1_1, and CgTpo3 in the clinical acquisition of clotrimazole drug resistance. A screening for azole drug resistance in 138 C. glabrata clinical isolates, from patients attending two major Hospitals in Portugal, was performed. Based on this screening, 10 clotrimazole susceptible and 10 clotrimazole resistant isolates were selected for further analysis. The transcript levels of CgAQR1, CgQDR2, CgTPO1_1, and CgTPO3 were found to be significantly up-regulated in resistant isolates when compared to the susceptible ones, with a level of correlation that was found to be similar to that of CgCDR2, an ABC gene known to be involved in the clinical acquisition of resistance. As a proof-of-concept experiment, the CgTPO3 gene was deleted in an azole resistant C. glabrata isolate, exhibiting high levels of expression of this gene. The deletion of CgTPO3 in this isolate was found to lead to decreased resistance to clotrimazole and fluconazole, and increased accumulation of azole drugs, thus suggesting the involvement of this transporter in the manifestation of azole resistance.
Highlights
In recent years, Candida glabrata has become the second most common cause of mucosal and invasive candidosis, only surpassed by C. albicans (Vermitsky and Edlind, 2004; Rodrigues et al, 2014; Yapar, 2014)
In what concerns CLT, 53.3% of the isolates coming from Hospital of Santa Maria (HSM) were found to be resistant, while isolates harvested in Centro Hospitalar São João (CHSJ) had a much higher incidence of clotrimazole-resistance (77.8%)
The participation of five multidrug transporters of the major facilitator superfamily (MFS) superfamily in the acquisition of clotrimazole resistance was evaluated in C. glabrata clinical isolates
Summary
Candida glabrata has become the second most common cause of mucosal and invasive candidosis, only surpassed by C. albicans (Vermitsky and Edlind, 2004; Rodrigues et al, 2014; Yapar, 2014). Drug:H+ Antiporters and Clinical Azole Resistance antifungal drugs both as treatment and prophylaxis has led to a huge increase in the number of intrinsically resistant infections with fungal pathogens. It has been shown that prolonged fluconazole exposure may favor the up rise of C. glabrata infections (Abbes et al, 2013; Papon et al, 2013) Both drugs act by inhibiting lanosterol 14α-demethylase, product of the ERG11 gene (Vermitsky and Edlind, 2004), a key enzyme in ergosterol biosynthesis. A disturbing percentage of the C. glabrata clinical isolates have been shown to display azole resistance, unlike what has been observed for most other Candida species (Sanguinetti et al, 2005). In a study involving 33 C. glabrata isolates, 20 were found to be resistant to fluconazole and ketoconazole (Sanguinetti et al, 2005)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
