scholarly journals Role of ATP-Binding-Cassette Transporter Genes in High-Frequency Acquisition of Resistance to Azole Antifungals in Candida glabrata

2001 ◽  
Vol 45 (4) ◽  
pp. 1174-1183 ◽  
Author(s):  
Dominique Sanglard ◽  
Francoise Ischer ◽  
Jacques Bille
Keyword(s):  
Abc Transporter ◽  
High Frequency ◽  
Candida Glabrata ◽  
Antifungal Agents ◽  
Clinical Isolates ◽  
Azole Resistance ◽  
Atp Binding ◽  
Transporter Gene ◽  
Atp Binding Cassette

ABSTRACT Candida glabrata has been often isolated from AIDS patients with oropharyngeal candidiasis treated with azole antifungal agents, especially fluconazole. We recently showed that the ATP-binding-cassette (ABC) transporter gene CgCDR1 was upregulated in C. glabrata clinical isolates resistant to azole antifungal agents (D. Sanglard, F. Ischer, D. Calabrese, P. A. Majcherczyk, and J. Bille, Antimicrob. Agents Chemother. 43:2753–2765, 1999). Deletion of CgCDR1 in C. glabrata rendered the null mutant hypersusceptible to azole derivatives and showed the importance of this gene in mediating azole resistance. We observed that wild-type C. glabrata exposed to fluconazole in a medium containing the drug at 50 μg/ml developed resistance to this agent and other azoles at a surprisingly high frequency (2 × 10−4 to 4 × 10−4). We show here that this high-frequency azole resistance (HFAR) acquired in vitro was due, at least in part, to the upregulation ofCgCDR1. The CgCDR1 deletion mutant DSY1041 could still develop HFAR but in a medium containing fluconazole at 5 μg/ml. In the HFAR strain derived from DSY1041, a distinct ABC transporter gene similar to CgCDR1, calledCgCDR2, was upregulated. This gene was slightly expressed in clinical isolates but was upregulated in strains with the HFAR phenotype. Deletion of both CgCDR1 and CgCDR2suppressed the development of HFAR in a medium containing fluconazole at 5 μg/ml, showing that both genes are important mediators of resistance to azole derivatives in C. glabrata. We also show here that the HFAR phenomenon was linked to the loss of mitochondria in C. glabrata. Mitochondrial loss could be obtained by treatment with ethidium bromide and resulted in acquisition of resistance to azole derivatives without previous exposure to these agents. Azole resistance obtained in vitro by HFAR or by agents stimulating mitochondrial loss was at least linked to the upregulation of both CgCDR1 and CgCDR2.

The ATP Binding Cassette Transporter GeneCgCDR1 from Candida glabrata Is Involved in the Resistance of Clinical Isolates to Azole Antifungal Agents

1999 ◽  
Vol 43 (11) ◽  
pp. 2753-2765 ◽  
Author(s):  
Dominique Sanglard ◽  
Françoise Ischer ◽  
David Calabrese ◽  
Paul A. Majcherczyk ◽  
Jacques Bille
Keyword(s):  
Clinical Isolate ◽  
Abc Transporter ◽  
Candida Glabrata ◽  
Antifungal Agents ◽  
Clinical Isolates ◽  
Azole Resistance ◽  
Atp Binding ◽  
Transporter Gene ◽  
Azole Antifungals ◽  
Susceptible Isolate

ABSTRACT The resistance mechanisms to azole antifungal agents were investigated in this study with two pairs of Candida glabrata clinical isolates recovered from two separate AIDS patients. The two pairs each contained a fluconazole-susceptible isolate and a fluconazole-resistant isolate, the latter with cross-resistance to itraconazole and ketoconazole. Since the accumulation of fluconazole and of another unrelated substance, rhodamine 6G, was reduced in the azole-resistant isolates, enhanced drug efflux was considered as a possible resistance mechanism. The expression of multidrug efflux transporter genes was therefore examined in the azole-susceptible and azole-resistant yeast isolates. For this purpose, C. glabrata genes conferring resistance to azole antifungals were cloned in a Saccharomyces cerevisiaestrain in which the ATP binding cassette (ABC) transporter genePDR5 was deleted. Three different genes were recovered, and among them, only C. glabrata CDR1 (CgCDR1), a gene similar to the Candida albicans ABC transporterCDR genes, was upregulated by a factor of 5 to 8 in the azole-resistant isolates. A correlation between upregulation of this gene and azole resistance was thus established. The deletion ofCgCDR1 in an azole-resistant C. glabrataclinical isolate rendered the resulting mutant (DSY1041) susceptible to azole derivatives as the azole-susceptible clinical parent, thus providing genetic evidence that a specific mechanism was involved in the azole resistance of a clinical isolate. When CgCDR1obtained from an azole-susceptible isolate was reintroduced with the help of a centromeric vector in DSY1041, azole resistance was restored and thus suggested that a trans-acting mutation(s) could be made responsible for the increased expression of this ABC transporter gene in the azole-resistant strain. This study demonstrates for the first time the determinant role of an ABC transporter gene in the acquisition of resistance to azole antifungals by C. glabrata clinical isolates.

Effect of antifungals on itraconazole resistant Candida glabrata

2010 ◽  
Vol 5 (3) ◽  
pp. 318-323 ◽  
Author(s):  
Soňa Kucharíková ◽  
Patrick Dijck ◽  
Magdaléna Lisalová ◽  
Helena Bujdáková
Keyword(s):  
Amphotericin B ◽  
Biofilm Formation ◽  
Candida Glabrata ◽  
Antifungal Agents ◽  
Inhibitory Concentration ◽  
Clinical Isolates ◽  
Azole Resistance ◽  
Low Concentrations ◽  
Reduction Assay ◽  
Very High

AbstractIn the last decade, infections caused by Candida glabrata have become more serious, particularly due to its decreased susceptibility to azole derivatives and its ability to form biofilm. Here we studied the resistance profile of 42 C. glabrata clinical isolates to different azoles, amphotericin B and echinocandins. This work was also focused on the ability to form biofilm which plays a role in the development of antifungal resistance. The minimal inhibitory concentration testing to antifungal agents was performed according to the CLSI (Clinical and Laboratory Standards Institute) M27-A3 protocol. Quantification of biofilm was done by XTT reduction assay. All C. glabrata clinical isolates were resistant to itraconazole and sixteen also showed resistance to fluconazole. All isolates remained susceptible to voriconazole. Amphotericin B was efficient in a concentration range of 0.125–1 mg/L. The most effective antifungal agents were micafungin and caspofungin with the MIC100 values of ≤0.0313–0.125 mg/L. Low concentrations of these agents reduced biofilm formation as well. Our results show that resistance of different C. glabrata strains is azole specific and therefore a single azole resistance cannot be assumed to indicate general azole resistance. Echinocandins proved to have very high efficacy against clinical C. glabrata strains including those with ability to form biofilm.

scholarly journals In Silico Genome-Wide Analysis of the ATP-Binding Cassette Transporter Gene Family in Soybean (Glycine max L.) and Their Expression Profiling

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Awdhesh Kumar Mishra ◽  
Jinhee Choi ◽  
Muhammad Fazle Rabbee ◽  
Kwang-Hyun Baek
Keyword(s):  
Gene Family ◽  
Abc Transporter ◽  
Abc Transporters ◽  
In Silico ◽  
Gene Families ◽  
Protein Domain ◽  
Atp Binding ◽  
Transporter Gene ◽  
Genome Wide ◽  
Atp Binding Cassette

ATP-binding cassette (ABC) transporters constitute one of the largest gene families in all living organisms, most of which mediate transport across biological membranes by hydrolyzing ATP. However, detailed studies of ABC transporter genes in the important oil crop, soybean, are still lacking. In the present study, we carried out genome-wide identification and phylogenetic and transcriptional analyses of the ABC gene family in G. max. A total of 261 G. max ABC (GmABCs) genes were identified and unevenly localized onto 20 chromosomes. Referring to protein-domain orientation and phylogeny, the GmABC family could be classified into eight (ABCA-ABCG and ABCI) subfamilies and ABCG were the most abundantly present. Further, investigation of whole genome duplication (WGD) signifies the role of segmental duplication in the expansion of the ABC transporter gene family in soybean. The Ka/Ks ratio indicates that several duplicated genes are governed by intense purifying selection during evolution. In addition, in silico expression analysis based on RNA-sequence using publicly available database revealed that ABC transporters are differentially expressed in tissues and developmental stages and in dehydration. Overall, we provide an extensive overview of the GmABC transporter gene family and it promises the primary basis for the study in development and response to dehydration tolerance.

Genome-wide analysis of the ATP-binding cassette (ABC) transporter gene family in the silkworm, Bombyx mori

2012 ◽  
Vol 39 (7) ◽  
pp. 7281-7291 ◽  
Author(s):  
Xiaodong Xie ◽  
Tingcai Cheng ◽  
Genhong Wang ◽  
Jun Duan ◽  
Weihuan Niu ◽  
...  
Keyword(s):  
Gene Family ◽  
Bombyx Mori ◽  
Abc Transporter ◽  
Atp Binding ◽  
Transporter Gene ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
Silkworm Bombyx Mori ◽  
Atp Binding Cassette

scholarly journals Functional analysis of the ATP-binding cassette (ABC) transporter gene family of Tribolium castaneum

BMC Genomics ◽  
2013 ◽  
Vol 14 (1) ◽  
pp. 6 ◽  
Author(s):  
Gunnar Broehan ◽  
Tobias Kroeger ◽  
Marcé Lorenzen ◽  
Hans Merzendorfer
Keyword(s):  
Functional Analysis ◽  
Gene Family ◽  
Abc Transporter ◽  
Tribolium Castaneum ◽  
Atp Binding ◽  
Transporter Gene ◽  
Atp Binding Cassette

scholarly journals Genome-wide analysis of the ATP-binding cassette (ABC) transporter gene family in sea lamprey and Japanese lamprey

BMC Genomics ◽  
2015 ◽  
Vol 16 (1) ◽  
Author(s):  
Jianfeng Ren ◽  
Yu-Wen Chung-Davidson ◽  
Chu-Yin Yeh ◽  
Camille Scott ◽  
Titus Brown ◽  
...  
Keyword(s):  
Gene Family ◽  
Abc Transporter ◽  
Sea Lamprey ◽  
Atp Binding ◽  
Transporter Gene ◽  
Genome Wide Analysis ◽  
Genome Wide ◽  
Atp Binding Cassette
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