Publications (22)69.87 Total impact
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Article: The Candida glabrata sterol scavenging mechanism, mediated by the ATP-binding cassette transporter Aus1p, is regulated by iron limitation.
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ABSTRACT: During disseminated infection by the opportunistic pathogen Candida glabrata, uptake of sterols such as serum cholesterol may play a significant role during pathogenesis. The ATP-binding cassette transporter Aus1p is thought to function as a sterol importer and in this study, we show that uptake of exogenous sterols occurred under anaerobic conditions in wild type cells of C. glabrata but not in AUS1-deleted mutant (aus1Δ) cells. In aerobic cultures, growth inhibition by fluconazole was prevented in the presence of serum, and AUS1 expression was up-regulated. Uptake of sterol by azole treated cells required the presence of serum, and sterol alone did not reverse FLC inhibition of growth. However, if iron availability in the growth medium was limited by addition of the iron chelators ferrozine or apo-transferrin, growth of wild-type cells, but not aus1Δ cells, was rescued. In a mouse model of disseminated infection, the Candida glabrata aus1Δ strain caused a significantly decreased kidney fungal burden than the wild type strain or a strain in which AUS1 was restored. We conclude that sterol uptake in C. glabrata can occur in iron poor environment of host tissues and thus may contribute to C. glabrata pathogenesis.Molecular Microbiology 02/2013; · 5.01 Impact Factor -
Article: Application of nested PCR for diagnosis of histoplasmosis.
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ABSTRACT: Histoplasmosis is a fungal infection that, although not endemic in Japan, has seen a rise in the number of Japanese cases since the mid-1980s. Diagnosis of the disease is not straightforward, and the main method of detection, fungal culture (which has biosafety-related issues), is of low sensitivity in general. Alternative methods that depend on antibody or antigen detection have had limited use. We have developed a histoplasmosis detection method based on PCR amplification of the Histoplasma capsulatum M antigen gene. We compared this method with fungal culture and serological diagnostic techniques. Among five cases that were finally diagnosed as histoplasmosis, the fungal culture method was only successful in identifying one such case. Although the presence of anti-H. capsulatum antibodies was confirmed in three cases, our PCR method identified four of five cases of histoplasmosis. The performance of our PCR method could not be compared with the antigen detection method, which is used in the United States but is not routinely used in Japan. However, the PCR method was shown to have high sensitivity and specificity for H. capsulatum. Although the number of histoplasmosis cases examined in this study was small, our data suggest that the molecular diagnosis technique has potential for increasing the reliability of histoplasmosis diagnosis when used in combination with established methods.Journal of Infection and Chemotherapy 01/2013; · 1.80 Impact Factor -
Article: Determination of Epidemiology of Clinically Isolated Cryptococcus neoformans Strains in Japan by Multilocus Sequence Typing.
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ABSTRACT: Cryptococcus neoformans and Cryptococcus gattii are the causative agents of cryptococcosis. Despite its importance, our knowledge of the epidemiology of cryptococcosis in Japan remains limited. To establish an epidemiological database on cryptococcosis in Japan, we determined the genetic variability of 44 Japanese clinical isolates of C. neoformans (var. grubii: serotype A) by multilocus sequence typing (MLST). The strains were clinically isolated from 1992 to 2011 in 5 different areas of Japan (the Hokkaido region [n = 1], Kanto region [n = 32], Chubu region [n = 1], Kansai region [n = 1], and Kyushu region [n = 9]). According to the method recommended by the International Society for Human and Animal Mycology cryptococcal genotyping working group, 36 isolates (82%) were identified as sequence type (ST)46. The remaining strains belonged to ST45 (n = 1) and ST47 (n = 1), and 6 isolates belonged to novel independent STs. There was little geographic difference in the ST population. Our present data are still limited; however, because most clinical isolates showed the same MLST profile in Japan, applying the current MLST scheme for Cryptococcus may at times be insufficient for investigating the infection route among outbreak cases. To solve this problem, it may be necessary to investigate other gene loci or develop a novel method with greater discriminatory power. However, in cases in which a strain belongs to a minor ST, our data may serve as useful epidemiological information in Japan.Japanese journal of infectious diseases. 01/2013; 66(1):51-5. -
Article: Serum cholesterol promotes the growth of Candida glabrata in the presence of fluconazole.
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ABSTRACT: The pathogenic fungus Candida glabrata is thought to utilize extracellular sterols during infection, but there have been few reports on the sterol uptake mechanisms of this fungus. The addition of serum promoted the growth of C. glabrata cells in the presence of the sterol inhibitor fluconazole, probably as the result of incorporation of cholesterol from serum. We demonstrated that lipoprotein-deficient serum, in which most of the cholesterol was eliminated, could not rescue the growth of fluconazole-treated C. glabrata cells, but it successfully promoted the expression of the sterol transporter gene AUS1. After supplementation of free cholesterol to lipoprotein-deficient serum, the serum was again competent to promote the growth of fluconazole-treated C. glabrata. The serum-mediated growth rescue from fluconazole inhibition was observed in the nonpathogenic yeast Saccharomyces cerevisiae when it was followed by the activation of anaerobic sterol uptake. These results suggested that serum cholesterol was incorporated into yeast cells to compensate for sterol depletion when sterol uptake was activated. The uptake of serum cholesterol could support the growth of C. glabrata cells during bloodstream infections.Journal of Infection and Chemotherapy 12/2012; · 1.80 Impact Factor -
Article: Chimeras of Candida albicans Cdr1p and Cdr2p reveal features of pleiotropic drug resistance transporter structure and function
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ABSTRACT: Members of the pleiotropic drug resistance (PDR) family of ATP binding cassette (ABC) transporters consist of two homologous halves, each containing a nucleotide binding domain (NBD) and a transmembrane domain (TMD). The PDR transporters efflux a variety of hydrophobic xenobiotics and despite the frequent association of their overexpression with the multidrug resistance of fungal pathogens, the transport mechanism of these transporters is poorly understood. Twenty-eight chimeric constructs between Candida albicans Cdr1p (CaCdr1p) and Cdr2p (CaCdr2p), two closely related but functionally distinguishable PDR transporters, were expressed in Saccharomyces cerevisiae. All chimeras expressed equally well, localized properly at the plasma membrane, retained their transport ability, but their substrate and inhibitor specificities differed significantly between individual constructs. A detailed characterization of these proteins revealed structural features that contribute to their substrate specificities and their transport mechanism. It appears that most transmembrane spans of CaCdr1p and CaCdr2p provide or affect multiple, probably overlapping, substrate and inhibitor binding site(s) similar to mammalian ABC transporters. The NBDs, in particular NBD1 and/or the ∼150 amino acids N-terminal to NBD1, can also modulate the substrate specificities of CaCdr1p and CaCdr2p.Molecular Microbiology 09/2011; 82(2):416 - 433. · 5.01 Impact Factor -
Article: Growth defects resulting from inhibiting ERG20 and RAM2 in Candida glabrata
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ABSTRACT: Farnesyl pyrophosphate (FPP) is utilized for many cellular processes, including the production of dolichols, ubiquinone (CoQ), sterols, farnesylated heme A and prenylated proteins. This lipid synthesized by FPP synthetase (ERG20) becomes attached to target proteins by the prenyltransferases, CDC43/RAM2 and RAM1/RAM2 complexes after the formation of the C15 and C20 units, respectively. Defects in protein prenylation as a result of inhibiting these enzyme complexes lead to pleiotropic effects in all eukaryotes. In this study, using Candida glabrata conditional mutants, the importance of the ERG20 and RAM2 genes for growth using both in vivo and in vitro assays was assessed by placing the RAM2 and ERG20 genes under the control of a regulatable promoter. Repression of RAM2 gene expression revealed growth defects under both conditions. However, repression of ERG20 gene expression did not impair fungal growth in a mouse host, but did result in growth defects on laboratory media. Thus, FPP synthase is not required for survival in an infected mouse, but the RAM2-encoded prenyltransferase was critical for growth under both conditions. This study strongly suggests that inhibitors of prenyltransferase may be promising antifungals.FEMS Microbiology Letters 01/2011; 317(1):27 - 33. · 2.04 Impact Factor -
Article: Transcription factors CgUPC2A and CgUPC2B regulate ergosterol biosynthetic genes in Candida glabrata.
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ABSTRACT: Zn[2]-Cys[6] binuclear transcription factors Upc2p and Ecm22p regulate the expression of genes involved in ergosterol biosynthesis and exogenous sterol uptake in Saccharomyces cerevisiae. We identified two UPC2/ECM22 homologues in the pathogenic fungus Candida glabrata which we designated CgUPC2A and CgUPC2B. The contribution of these two genes to sterol homeostasis was investigated. Cells that lack CgUPC2A (upc2AΔ) exhibited enhanced susceptibility to the sterol biosynthesis inhibitors, fluconazole and lovastatin, whereas upc2BΔ-mutant cells were as susceptible to the drugs as wild-type cells. The growth of upc2AΔ cells was also severely attenuated under anaerobic conditions. Lovastatin treatment enhanced the expression of ergosterol biosynthetic genes, ERG2 and ERG3 in wild-type and upc2BΔ but not in upc2AΔ cells. Similarly, serum-induced expression of ERG2 and ERG3 was completely impaired in upc2AΔ cells but was unaffected in upc2BΔ cells, whereas serum-induced expression of the sterol transporter gene CgAUS1 was impaired in both upc2AΔ and upc2BΔ cells. These results suggest that in C. glabrata CgUPC2A but not in CgUPC2B is the main transcriptional regulator of the genes responsible for maintaining sterol homeostasis as well as susceptibility to sterol inhibitors.Genes to Cells 01/2011; 16(1):80-9. · 2.68 Impact Factor -
Article: Transcription factors CgUPC2A and CgUPC2B regulate ergosterol biosynthetic genes in Candida glabrata
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ABSTRACT: Zn[2]-Cys[6] binuclear transcription factors Upc2p and Ecm22p regulate the expression of genes involved in ergosterol biosynthesis and exogenous sterol uptake in Saccharomyces cerevisiae. We identified two UPC2/ECM22 homologues in the pathogenic fungus Candida glabrata which we designated CgUPC2A and CgUPC2B. The contribution of these two genes to sterol homeostasis was investigated. Cells that lack CgUPC2A (upc2AΔ) exhibited enhanced susceptibility to the sterol biosynthesis inhibitors, fluconazole and lovastatin, whereas upc2BΔ-mutant cells were as susceptible to the drugs as wild-type cells. The growth of upc2AΔ cells was also severely attenuated under anaerobic conditions. Lovastatin treatment enhanced the expression of ergosterol biosynthetic genes, ERG2 and ERG3 in wild-type and upc2BΔ but not in upc2AΔ cells. Similarly, serum-induced expression of ERG2 and ERG3 was completely impaired in upc2AΔ cells but was unaffected in upc2BΔ cells, whereas serum-induced expression of the sterol transporter gene CgAUS1 was impaired in both upc2AΔ and upc2BΔ cells. These results suggest that in C. glabrata CgUPC2A but not in CgUPC2B is the main transcriptional regulator of the genes responsible for maintaining sterol homeostasis as well as susceptibility to sterol inhibitors.Genes to Cells 12/2010; 16(1):80 - 89. · 2.68 Impact Factor -
Article: Serum or bile affects the in vitro azole susceptibilities of Candida spp.
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ABSTRACT: Drug susceptibility tests were performed with a series of Candida spp. in media supplemented with serum or bile. The azole susceptibilities of several medically important Candida spp., including C. albicans but not C. parapsilosis, were significantly reduced in supplemented media. These findings have important implications for the mechanisms of acquired azole resistance in pathogenic fungi.Japanese journal of infectious diseases 08/2009; 62(4):306-8. · 1.49 Impact Factor -
Article: Efflux-mediated antifungal drug resistance.
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ABSTRACT: Fungi cause serious infections in the immunocompromised and debilitated, and the incidence of invasive mycoses has increased significantly over the last 3 decades. Slow diagnosis and the relatively few classes of antifungal drugs result in high attributable mortality for systemic fungal infections. Azole antifungals are commonly used for fungal infections, but azole resistance can be a problem for some patient groups. High-level, clinically significant azole resistance usually involves overexpression of plasma membrane efflux pumps belonging to the ATP-binding cassette (ABC) or the major facilitator superfamily class of transporters. The heterologous expression of efflux pumps in model systems, such Saccharomyces cerevisiae, has enabled the functional analysis of efflux pumps from a variety of fungi. Phylogenetic analysis of the ABC pleiotropic drug resistance family has provided a new view of the evolution of this important class of efflux pumps. There are several ways in which the clinical significance of efflux-mediated antifungal drug resistance can be mitigated. Alternative antifungal drugs, such as the echinocandins, that are not efflux pump substrates provide one option. Potential therapeutic approaches that could overcome azole resistance include targeting efflux pump transcriptional regulators and fungal stress response pathways, blockade of energy supply, and direct inhibition of efflux pumps.Clinical microbiology reviews 05/2009; 22(2):291-321, Table of Contents. · 14.69 Impact Factor -
Article: [What's new in the molecular basis of antifungal drug resistance in pathogenic yeasts].
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ABSTRACT: Drug resistance in various organisms including cancer cells, bacteria and fungi is a serious issue for human disease therapy, including use of anticancer drugs, antibiotics and antifungals, respectively. Candida strains resistant to the azole class of antifungal drugs, have been isolated frequently from HIV patients following prophylaxis with azole drugs such as fluconazole. Therefore, it is important to be aware of the emergence of drug-resistant clinical isolates, despite the recent introduction of new, effective classes of antifungal drugs such as the azole voriconazole, and the candin micafungin. In this review we discuss the molecular mechanisms underlying resistance to the azole and candin antifungal agents.Nippon rinsho. Japanese journal of clinical medicine 01/2009; 66(12):2273-8. -
Article: ABC transporter Cdr1p contributes more than Cdr2p does to fluconazole efflux in fluconazole-resistant Candida albicans clinical isolates.
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ABSTRACT: Fluconazole (FLC) remains the antifungal drug of choice for non-life-threatening Candida infections, but drug-resistant strains have been isolated during long-term therapy with azoles. Drug efflux, mediated by plasma membrane transporters, is a major resistance mechanism, and clinically significant resistance in Candida albicans is accompanied by increased transcription of the genes CDR1 and CDR2, encoding plasma membrane ABC-type transporters Cdr1p and Cdr2p. The relative importance of each transporter protein for efflux-mediated resistance in C. albicans, however, is unknown; neither the relative amounts of each polypeptide in resistant isolates nor their contributions to efflux function have been determined. We have exploited the pump-specific properties of two antibody preparations, and specific pump inhibitors, to determine the relative expression and functions of Cdr1p and Cdr2p in 18 clinical C. albicans isolates. The antibodies and inhibitors were standardized using recombinant Saccharomyces cerevisiae strains that hyper-express either protein in a host strain with a reduced endogenous pump background. In all 18 C. albicans strains, including 13 strains with reduced FLC susceptibilities, Cdr1p was present in greater amounts (2- to 20-fold) than Cdr2p. Compounds that inhibited Cdr1p-mediated function, but had no effect on Cdr2p efflux activity, significantly decreased the resistance to FLC of seven representative C. albicans isolates, whereas three other compounds that inhibited both pumps did not cause increased chemosensitization of these strains to FLC. We conclude that Cdr1p expression makes a greater functional contribution than does Cdr2p to FLC resistance in C. albicans.Antimicrobial Agents and Chemotherapy 09/2008; 52(11):3851-62. · 4.84 Impact Factor -
Article: The Candida glabrata putative sterol transporter gene CgAUS1 protects cells against azoles in the presence of serum.
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ABSTRACT: The uptake of endogenous sterol from serum may allow Candida glabrata to survive azole treatment. This study aims to determine the contribution of a sterol transporter that alters fluconazole sensitivity in the presence of serum. Bioinformatic analysis predicted CgAUS1 as the C. glabrata orthologue of the Saccharomyces cerevisiae transporters AUS1 and PDR11. To investigate whether the CgAUS1 gene has sterol transporter activity, we investigated the effects of an AUS1 deletion on the growth of a tetracycline-regulatable ERG9 strain (tet-ERG9aus1), wherein ERG9 expression is turned off giving rise to a sterol requirement. Tetracycline-dependent repression of CgAUS1 in the tet-AUS1 strain was used to determine the fluconazole susceptibility of CgAUS1 in the presence and absence of serum. The tetracycline-treated tet-ERG9aus1 strain failed to grow in the presence of serum, whereas the parental tet-ERG9AUS1 strain grew by incorporating sterol from exogenously supplied serum. Serum cholesterol protected cells against the antifungal effects of fluconazole and this protection was lost by repressing CgAUS1 gene expression. Furthermore, such protection was also observed during itraconazole treatment, but not observed in cells treated with non-azole antifungals. CgAUS1 appears to function as a sterol transporter that may contribute to lower azole susceptibility in the presence of serum and to protect C. glabrata against azole toxicity in vivo.Journal of Antimicrobial Chemotherapy 01/2008; 60(6):1264-72. · 5.07 Impact Factor -
Article: Inhibition of fungal ABC transporters by unnarmicin A and unnarmicin C, novel cyclic peptides from marine bacterium.
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ABSTRACT: Novel inhibitors of fungal ATP-binding cassette transporters were obtained by screening compounds and crude extracts from marine-derived fungi and bacteria using disk diffusion assays of Saccharomyces cerevisiae strains overexpressing a variety of fungal multi-drug efflux pumps. The cyclodepsipeptides unnarmicin A and unnarmicin C were able to sensitize cells overexpressing azole drug pumps ScPdr5p, CaCdr1p, CgCdr1p, and CgPdh1p to sub-MIC concentrations of fluconazole without affecting the growth of CaCdr2p and CaMdr1p overexpressing cells. Unnarmicin A and unnarmicin C were potent inhibitors of rhodamine 6G efflux of CaCdr1p expressing cells with IC50 values of 3.61 and 5.65 microM, respectively. They inhibited the in vitro CaCdr1p ATPase activity at IC50 values of 0.495 and 0.688 microM, respectively. And most importantly, they were able to sensitize azole-resistant Candida albicans clinical isolates to fluconazole. Unnarmicin A and unnarmicin C are candidate efflux pump inhibitors with the potential to be used as adjuvants for antifungal chemotherapy.Biochemical and Biophysical Research Communications 01/2008; 364(4):990-5. · 2.48 Impact Factor -
Article: Candida albicans drug resistance another way to cope with stress.
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ABSTRACT: There are relatively few classes of antifungal drugs. This restricts clinicians' therapeutic choices and these choices are further reduced by the emergence of drug resistance. Exposure to antifungal drugs represents an environmental stress for the fungal pathogen Candida albicans. The immediate response of C. albicans to antifungals may be drug tolerance, which can lead to drug resistance. This article examines C. albicans drug resistance from the perspective of it being a stress response and investigates how commonality with other stress-response pathways gives insights into the prospects for overcoming, or preventing, drug resistance.Microbiology 11/2007; 153(Pt 10):3211-7. · 3.06 Impact Factor -
Article: Characterization of three classes of membrane proteins involved in fungal azole resistance by functional hyperexpression in Saccharomyces cerevisiae.
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ABSTRACT: The study of eukaryotic membrane proteins has been hampered by a paucity of systems that achieve consistent high-level functional protein expression. We report the use of a modified membrane protein hyperexpression system to characterize three classes of fungal membrane proteins (ABC transporters Pdr5p, CaCdr1p, CaCdr2p, CgCdr1p, CgPdh1p, CkAbc1p, and CneMdr1p, the major facilitator superfamily transporter CaMdr1p, and the cytochrome P450 enzyme CaErg11p) that contribute to the drug resistance phenotypes of five pathogenic fungi and to express human P glycoprotein (HsAbcb1p). The hyperexpression system consists of a set of plasmids that direct the stable integration of a single copy of the expression cassette at the chromosomal PDR5 locus of a modified host Saccharomyces cerevisiae strain, ADDelta. Overexpression of heterologous proteins at levels of up to 29% of plasma membrane protein was achieved. Membrane proteins were expressed with or without green fluorescent protein (GFP), monomeric red fluorescent protein, His, FLAG/His, Cys, or His/Cys tags. Most GFP-tagged proteins tested were correctly trafficked within the cell, and His-tagged proteins could be affinity purified. Kinetic analysis of ABC transporters indicated that the apparent K(m) value and the V(max) value of ATPase activities were not significantly affected by the addition of His tags. The efflux properties of seven fungal drug pumps were characterized by their substrate specificities and their unique patterns of inhibition by eight xenobiotics that chemosensitized S. cerevisiae strains overexpressing ABC drug pumps to fluconazole. The modified hyperexpression system has wide application for the study of eukaryotic membrane proteins and could also be used in the pharmaceutical industry for drug screening.Eukaryotic Cell 08/2007; 6(7):1150-65. · 3.60 Impact Factor -
Article: Amino acid residues affecting drug pump function in Candida albicans--C. albicans drug pump function.
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ABSTRACT: Membrane-located drug transporters are important components in the multidrug resistance of microbial cells and human tissues. In fungi, clinically important resistance to antifungal drugs most often results from the over-expression of efflux pump proteins in the plasma membrane of the resistant cell. This review describes studies of the ATP binding cassette (ABC) family of membrane efflux pumps in the opportunistic human pathogen Candida albicans and, in particular, examines how changes in the polypeptide sequence can affect pump function. The identification of amino acid residues affecting pump function can provide new insights into efflux pump mechanisms and the relationship between structure and function. Such information will be important for the design of pump inhibitors which could supplement existing antifungal drugs.Nippon Ishinkin Gakkai Zasshi 02/2006; 47(4):275-81. -
Article: Characterization of the Saccharomyces cerevisiae sec6-4 mutation and tools to create S. cerevisiae strains containing the sec6-4 allele.
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ABSTRACT: The highly conserved exocyst complex of eukaryotic cells allows the polarized transport and fusion of late secretory vesicles with the plasma membrane. In Saccharomyces cerevisiae the Sec6p component of the exocyst complex is essential for cell growth. The sec6-4 temperature-sensitive mutation of the S. cerevisiae SEC6 gene leads to the accumulation of large amounts of mature late post-Golgi secretory vesicles in the cytosol of mutant cells at the restrictive temperature of 37 degrees C. These readily isolated, inside-out and tightly sealed vesicles contain mature post-translationally modified plasma membrane and secretory proteins and provide a valuable tool for the study of plasma membrane protein function. This study shows that the single point mutation L633P in the SEC6 coding region defines the sec6-4 phenotype. We followed the localization of the wild type Sec6p and the mutant Sec6-4p proteins (C-terminally tagged with the green fluorescent protein yEGfp3p) in the presence or absence of heterologously over-expressed Candida albicans plasma membrane ATP-binding cassette (ABC) transporter CaCdr1p (C-terminally tagged with the red fluorescent protein mRfp1p). The Sec6-4p protein localized to buds and septa, like wild type Sec6p, at the permissive temperature of 23 degrees C and the sec6-4 mutant cells grew at the same rate as the wild type control cells. Sec6-4p was mislocalized at the restrictive temperature of 37 degrees C and heterogenous vesicles accumulated in cells but sec6-4 cells also accumulated homogenous secretory vesicles at the permissive temperature.Gene 12/2005; 361:57-66. · 2.34 Impact Factor -
Article: Functional analysis of fungal drug efflux transporters by heterologous expression in Saccharomyces cerevisiae.
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ABSTRACT: Clinically important resistance of fungal pathogens to azole antifungal drugs is most frequently caused by the over-expression of energy-dependent drug efflux pumps. These pumps usually belong to either the ATP-binding cassette (ABC) family or the Major Facilitator Superfamily (MFS) class of membrane transporter. Little is known about how these pumps work and there is an urgent need to develop pump antagonists that circumvent azole resistance. We have developed a protein hyper-expression system to facilitate functional analysis of efflux pumps based on a Saccharomyces cerevisiae host which has been deleted in seven major ABC transporters to reduce the background of endogenous efflux activity. Plasmid pABC3 was engineered to allow functional hyper-expression of foreign proteins in this host. The main advantages of the system include its ease of directional cloning and the use of homologous recombination to stably integrate single copy constructs into the host genome under the control of a highly active transcriptional regulator. The system has been used to clone and functionally hyper-express genes encoding drug efflux pumps from several pathogenic fungi. Furthermore, the protein hyper-expression system has been used to screen for pump inhibitors and study the structure and function of heterologous membrane proteins.Japanese journal of infectious diseases 03/2005; 58(1):1-7. · 1.49 Impact Factor -
Article: [ABC transporters of pathogenic fungi: recent advances in functional analyses].
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ABSTRACT: ABC (ATP binding cassette) transporters consist of transmembrane domains which confer specificity, and structurally conserved nucleotide binding domains that contain highly conserved amino acid motifs. They act not only as transporters but also as receptors or channels that use energy generated by ATP hydrolysis. ABC transporters are widely dispersed in nature. They are found in cells ranging from prokaryotes (bacteria) to eukaryotes (including humans) and several are considered to play crucial roles in cellular homeostasis. Defects in ABC transporters in humans are associated with severe diseases such as type 2 diabetes and cystic fibrosis. Some ABC transporters extrude xenobiotics and confer resistance to chemotherapeutics on microbial pathogens and cancer cells. Thus ABC transporters are of considerable medical importance. Structure-function analysis of ABC transporters has begun to elucidate their mechanisms of substrate recognition, the functional regulation of ATP-binding and hydrolysis and to identify intrinsic physiological functions. In pathogenic fungi, ABC transporters contribute to the clinical problem of drug resistance. The application of new technologies to the examination of fungal ABC transporter function is providing new insights into the use of antifungal drugs in medical mycology and contributing to a better understanding of these important membrane proteins.Nippon Ishinkin Gakkai Zasshi 02/2005; 46(4):249-60.
Top co-authors
Top Journals
Institutions
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2005–2013
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National Institute of Infectious Diseases, Tokyo
Tokyo, Tokyo-to, Japan
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2005–2009
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The University of Otago
- • Faculty of Dentistry
- • Department of Oral Sciences
Dunedin, Otago, New Zealand
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