Efflux Pumps in Drug Resistance of Candida

Prasad, Rajendra; Gaur, Naseem A.; Gaur, Manisha; Komath, Sneha Sudha

doi:10.2174/187152606784112164

Cited by 61 publications

(57 citation statements)

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“…It is known that steroids can induce a PDR state in both Candida albicans and S. cerevisiae [15,16] and the Pdr5p and Snq2p proteins of S. cerevisiae are able to efflux steroid hormones. Thus, yeast PDR transporters, similar to human Mdr1p, could be involved in the total sterol homeostasis in yeast cells [17].…”

Section: Introductionmentioning

confidence: 99%

Putative role for ABC multidrug exporters in yeast quorum sensing

et al. 2009

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a b s t r a c tPleiotropic drug resistance (PDR) transporters play essential roles in cell resistance to various toxic compounds in various organisms including bacteria, mammals and yeasts. A large group of PDR transporters have been described in yeasts so far, including those that are controlled by transcription factor Pdr1p. Here, we show that besides their role in removing extracellularly added toxic compounds, the Pdr5p and Snq2p transporters play important physiological roles and significantly influence the developmental phases and physiology of yeast populations growing in a liquid culture. They appear to be involved in population quorum sensing, which consequently influences transcription factor Pdr1p level via feedback regulation.

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Section: Introductionmentioning

confidence: 99%

Putative role for ABC multidrug exporters in yeast quorum sensing

et al. 2009

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“…Notably, major multidrug transporters of Candida spp. belonging to different superfamilies, such as ABC or MFS, display promiscuity toward substrate specificity and use different mechanisms of drug extrusion (32). The regulatory circuits which control the gene expression of either ABC or MFS efflux proteins also are different (25,29,38).…”

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confidence: 99%

Ncb2 Is Involved in Activated Transcription of CDR1 in Azole-Resistant Clinical Isolates of Candida albicans

et al. 2011

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We recently demonstrated that CDR1 overexpression in azole-resistant isolates of Candida albicans is due to its enhanced transcriptional activation and increased mRNA stability. In this study, we provide the first evidence of transcriptional regulation of CDR1 by Ncb2, the ␤ subunit of NC2, a heterodimeric regulator of transcription. Conditional NCB2 null mutants displayed decreased susceptibility toward azole and an enhanced transcription of CDR1. Interestingly, Ncb2 associated with the CDR1 promoter under both repression and activation; however, an increase in recruitment was observed under both transient and constitutive activation states. By chromatin immunoprecipitation (ChIP) assay, we showed the preferential recruitment of Ncb2 to the core TATA region under activation (azole-resistant isolate), while under repression (azole-susceptible isolate) it was present at the TATA upstream region. Further, ChIP analysis revealed that Ncb2 binding was not restricted to the CDR1 gene; instead, it was observed on the promoters of genes coregulated with CDR1 by the transcription activator Tac1. The tac1⌬ null mutants, which fail to show the drug-induced transient activation of CDR1, also showed no increase in Ncb2 recruitment at the promoter. Taken together, our results show that Ncb2, in conjunction with Tac1, is involved in the transcriptional activation of CDR1, opening up new therapeutic possibilities to combat multidrug resistance (MDR) in C. albicans.Candida albicans is an opportunistic human pathogen which mostly infects immunocompromised patients. It has gained considerable importance due to its ability to acquire resistance to a wide range of drugs during the treatment of its infection. Among various mechanisms contributing to acquired resistance against antifungal agents, drug efflux represents an important strategy adopted by the pathogen (33,37,39,40,43,45). Thus, most of the clinical, multidrug-resistant (MDR) isolates of C. albicans are shown to overexpress CDR1, CDR2, or MDR1 drug efflux pump-encoding genes. Cdr1 and Cdr2 belong to the ATP-binding cassette (ABC) superfamily of transporters and use energy driven from ATP hydrolysis to functionally transport drugs outside the cells. Mdr1, on the other hand, is a proton/drug antiporter which belongs to the superfamily of major facilitators (MFS). Notably, major multidrug transporters of Candida spp. belonging to different superfamilies, such as ABC or MFS, display promiscuity toward substrate specificity and use different mechanisms of drug extrusion (32). The regulatory circuits which control the gene expression of either ABC or MFS efflux proteins also are different (25,29,38).The CDR1 gene encodes a major drug efflux protein which is regulated both transcriptionally and posttranscriptionally. The regulation of CDR1 has been extensively studied by us and other groups (4,5,6,8,18,21,35). It has been shown that the CDR1 promoter harbors various consensus cis elements (Sp1, AP-1, and Y-box) as well as specific cis-elements, such as as BRE, NRE (for Negative ...

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“…The substrate range of both membrane transporters is very broad and may include ions, amino acids, peptides, sugars, secondary metabolites and drugs. Several studies have investigated the role of the MDR transporter in response to metabolic poisons and antifungal drugs (Prasad et al, 2006). BLASTX analysis revealed the identity of a sequence that was highly upregulated in the test cDNA population (TR0044, GenBank accession no.…”

Section: Expression Of Transporter Genes In T Rubrummentioning

confidence: 99%

“…Furthermore, specific genes need to be expressed to enable these mechanisms, which are involved in the activation of signal transduction for maintenance of the infection process under keratin contact. The occurrence of therapeutic failures due to the development of resistance is often associated with efflux pumps in the cell membrane (Martinez-Rossi et al, 2008;Prasad et al, 2006). Recent observations have indicated that membrane transporters are commonly involved in bacterial and fungal pathogenesis, with important roles as virulence factors to ensure successful colonization in a host environment (Mishra et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Membrane transporter proteins are involved in Trichophyton rubrum pathogenesis

Maranhão

Paião

Fachin

et al. 2009

Journal of Medical Microbiology

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Trichophyton rubrum is a dermatophyte responsible for the majority of human superficial mycoses. The functional expression of proteins important for the initial step and the maintenance of the infection process were identified previously in T. rubrum by subtraction suppression hybridization after growth in the presence of keratin. In this study, sequences similar to genes encoding the multidrug-resistance ATP-binding cassette (ABC) transporter, copper ATPase, the major facilitator superfamily and a permease were isolated, and used in Northern blots to monitor the expression of the genes, which were upregulated in the presence of keratin. A sequence identical to the TruMDR2 gene, encoding an ABC transporter in T. rubrum, was isolated in these experiments, and examination of a T. rubrum DTruMDR2 mutant showed a reduction in infecting activity, characterized by low growth on human nails compared with the wild-type strain. The high expression levels of transporter genes by T. rubrum in mimetic infection and the reduction in virulence of the DTruMDR2 mutant in a disease model in vitro suggest that transporters are involved in T. rubrum pathogenicity.

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Efflux Pumps in Drug Resistance of Candida

Cited by 61 publications

References 0 publications

Putative role for ABC multidrug exporters in yeast quorum sensing

Putative role for ABC multidrug exporters in yeast quorum sensing

Ncb2 Is Involved in Activated Transcription of CDR1 in Azole-Resistant Clinical Isolates of Candida albicans

Membrane transporter proteins are involved in Trichophyton rubrum pathogenesis

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