Increased expression and hotspot mutations of the multidrug efflux transporter, CDR1 in azole-resistantCandida albicansisolates from vaginitis patients

Abstract

The aims of our research were to investigate the gene expression of the multidrug efflux transporter, CDR1 and the major drug facilitator superfamily transporter, MDR1 gene in azole drug-resistant Candida albicans and Candida glabrata clinical isolates recovered from vaginitis patients; and to identify hotspot mutations that may be present in the C. albicans CaCDR1 gene that could be associated with drug-resistance. The relative expression of the CDR1 and MDR1 transcripts in ketoconazole and clotrimazole-resistant isolates and drug-susceptible ATCC strains were determined by semi-quantitative reverse transcription-polymerase chain reaction. Expression of CaCDR1 transcript was upregulated to varying extents in all three azole-resistant C. albicans isolates studied (1.6-, 3.7- and 3.9-fold) and all three C. glabrata isolates tested (at 1.9-, 2.3- and 2.7-fold). The overexpression level of CaCDR1 in the isolates correlated with the degree of resistance as reflected by the minimum inhibitory concentration (MIC) of the drugs. The messenger RNA for another efflux pump, MDR1, was also overexpressed in one of the azole-resistant C. albicans isolates that overexpressed CDR1. This finding suggests that drug-resistance may involve synergy between energy-dependent drug efflux pumps CDR1p and MDR1p in some but not all isolates. Interestingly, DNA sequence analysis of the promoter region of the CaCDR1 gene revealed several point mutations in the resistant clinical isolates compared to the susceptible isolates at 39, 49 and 151 nucleotides upstream from the ATG start codon. This finding provides new information on point mutations in the promoter region which may be responsible for the overexpression of CDR1 in drug-resistant isolates.

Transient Receptor Potential Channels in Sensory Neurons Are Targets of the Antimycotic Agent Clotrimazole

“…Finally, it cannot be excluded that the some neurons have mechanisms that mediate rapid extrusion or breakdown of CLT and thereby prevent it from significantly activating TRPV1/TRPA1. For example, it has been shown in yeast that high expression of drug extrusion pumps such as multidrug resistance 1 (MDR1) can lead to resistance to CLT (White et al, 2002;Looi et al, 2005). Independent of the mechanism, the lower cellular sensitivity to CLT compared with capsaicin or MO matches with the milder perceived sensory effects of CLT when applied to the tongue or mucous membranes.…”

Management of Recurrent Vulvo-Vaginal Candidosis as a Chronic Illness

“…However, clear differences in resistance profiles were found between diabetic, pregnant and nonpregnant-nondiabetic patients [21] . Different mechanisms, like chromosomal mutations inducing specific antifungal resistance on the one hand [22] or the presence of fluconazole/triazole efflux pumps on the other [23] , may be rare causes of chronic Candida vulvo-vaginitis that are particularly recalcitrant to different therapeutic attempts. Usually, these patients can only be given some relief by trial-and-error nontriazole treatment efforts such as gentian violet, boric acid suppositories, or by using off-the-record antifungals like amphotericin B, fluomycin, voriconazole or caspofungin (J. Sobel, Wayne State University, Detroit, Mich., USA, and W. Mendling, Charity Hospital, Berlin, Germany [pers.…”

Comparison between efficacy of allicin and fluconazole against Candida albicans in vitro and in a systemic candidiasis mouse model

“…This increase over the last two decades has caused a rise in the use of antifungal drugs (Pereira-Cenci et al, 2008). However, one of the biggest problems faced in clinical practice is the emergence of resistance to most of these azole drugs due to mutation (Odds et al, 2003;Looi et al, 2005). However, one of the biggest problems faced in clinical practice is the emergence of resistance to most of these azole drugs due to mutation (Odds et al, 2003;Looi et al, 2005).…”

“…Azoles such as fluconazole or ketoconazole are usually used for treatment of systemic fungal infections. However, one of the biggest problems faced in clinical practice is the emergence of resistance to most of these azole drugs due to mutation (Odds et al, 2003;Looi et al, 2005). Clinically adverse effects are also seen with the use of azoles (Al-Mohsen & Hughes, 1998).…”