Antagonistic Changes in Sensitivity to Antifungal Drugs by Mutations of an Important ABC Transporter Gene in a Fungal Pathogen

College of Life Sciences, Zhejiang University, Hangzhou, People's Republic of China.
PLoS ONE (Impact Factor: 3.23). 06/2010; 5(6):e11309. DOI: 10.1371/journal.pone.0011309
Source: PubMed


Fungal pathogens can be lethal, especially among immunocompromised populations, such as patients with AIDS and recipients of tissue transplantation or chemotherapy. Prolonged usage of antifungal reagents can lead to drug resistance and treatment failure. Understanding mechanisms that underlie drug resistance by pathogenic microorganisms is thus vital for dealing with this emerging issue. In this study, we show that dramatic sequence changes in PDR5, an ABC (ATP-binding cassette) efflux transporter protein gene in an opportunistic fungal pathogen, caused the organism to become hypersensitive to azole, a widely used antifungal drug. Surprisingly, the same mutations conferred growth advantages to the organism on polyenes, which are also commonly used antimycotics. Our results indicate that Pdr5p might be important for ergosterol homeostasis. The observed remarkable sequence divergence in the PDR5 gene in yeast strain YJM789 may represent an interesting case of adaptive loss of gene function with significant clinical implications.

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Available from: Lars M Steinmetz, May 29, 2014
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    • "In contrast with Guan et al. (2010), we did not detect association between PDR5 and amphotericin B resistance. However, in agreement with Guan et al. (2010) "
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    ABSTRACT: Saccharomyces cerevisiae, a well-established model for species as diverse as humans and pathogenic fungi, is more recently a model for population and quantitative genetics. S. cerevisiae is found in multiple environments-one of which is the human body-as an opportunistic pathogen. To aid in the understanding of the S. cerevisiae population and quantitative genetics, as well as its emergence as an opportunistic pathogen, we sequenced, de novo assembled, and extensively manually edited and annotated the genomes of 93 S. cerevisiae strains from multiple geographic and environmental origins, including many clinical origin strains. These 93 S. cerevisiae strains, the genomes of which are near-reference quality, together with seven previously sequenced strains, constitute a novel genetic resource, the "100-genomes" strains. Our sequencing coverage, high-quality assemblies, and annotation provide unprecedented opportunities for detailed interrogation of complex genomic loci, examples of which we demonstrate. We found most phenotypic variation to be quantitative and identified population, genotype, and phenotype associations. Importantly, we identified clinical origin associations. For example, we found that an introgressed PDR5 was present exclusively in clinical origin mosaic group strains; that the mosaic group was significantly enriched for clinical origin strains; and that clinical origin strains were much more copper resistant, suggesting that copper resistance contributes to fitness in the human host. The 100-genomes strains are a novel, multipurpose resource to advance the study of S. cerevisiae population genetics, quantitative genetics, and the emergence of an opportunistic pathogen. © 2015 Strope et al.; Published by Cold Spring Harbor Laboratory Press.
    Genome Research 04/2015; 25(5). DOI:10.1101/gr.185538.114 · 14.63 Impact Factor
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    • "The phenotypes analyzed included relative growth in different carbon sources (glucose, ethanol, galactose, and glycerol) and growth in the presence of different drugs (4NQO, fluconazole, hydroxyurea, and nystatin) (Fig. 1A). Fluconazole and nystatin both affect sterol metabolism, and YJM789 sensitivity to these chemicals has been recently linked to polymorphisms in the multidrug transporter Pdr5 (Guan et al. 2010). The genetic variation of response to hydroxyurea remains unknown. "
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    ABSTRACT: Genetic basis of phenotypic differences in individuals is an important area in biology and personalized medicine. Analysis of divergent Saccharomyces cerevisiae strains grown under different conditions revealed extensive variation in response to both drugs (e.g., 4-nitroquinoline 1-oxide [4NQO]) and different carbon sources. Differences in 4NQO resistance were due to amino acid variation in the transcription factor Yrr1. Yrr1(YJM789) conferred 4NQO resistance but caused slower growth on glycerol, and vice versa with Yrr1(S96), indicating that alleles of Yrr1 confer distinct phenotypes. The binding targets of Yrr1 alleles from diverse yeast strains varied considerably among different strains grown under the same conditions as well as for the same strain under different conditions, indicating that distinct molecular programs are conferred by the different Yrr1 alleles. Our results demonstrate that genetic variations in one important control gene (YRR1), lead to distinct regulatory programs and phenotypes in individuals. We term these polymorphic control genes "master variators."
    Genes & development 02/2014; 28(4):409-21. DOI:10.1101/gad.228940.113 · 10.80 Impact Factor
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    • "Sanglard et al. analyzed the gene expression profiles of azole-resistant C. albicans isolates treated with azole drugs and showed CaCDR -specific up-regulation of CaERG3 and CaERG6 which are involved in ergosterol biosynthesis (Karababa et al. 2004). Guan et al. (2010) observed that loss of pdr5p function due to mutations causes azole susceptibility and AmB resistance. In our study, we directly demonstrate the relationship between ergosterol and efflux pumps in C. albicans as well as in S. cerevisiae. "
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    ABSTRACT: Most screening approaches produce compounds that target survival genes and are likely to generate resistance over time. Simply having more drugs does not address the potential emergence of resistance caused by target mutation, drug efflux pumps over-expression, and so on. There is a great need to explore new strategies to treat fungal infections caused by drug-resistant pathogens. In this study, we found that azole-resistant Candida albicans with CaCDR1 and CaCDR2 over-expression is hypersensitive against amphotericin B (AmB) by our high throughput synergy screening (HTSS). In contrast, Δcdr1 and Δcdr2 knockout strains were resistant to AmB. Moreover, clinical isolates with increased expression of CaCDR1 and CaCDR2 demonstrated susceptibility to AmB, which can also synergize with the efflux pumps inducer fluphenazine (FPZ). Finally, the increased drug susceptibility to AmB in azole-resistant C. albicans with drug efflux pumps over-expression was consistent with the elevated expression of CaERG11 and its associated ergosterols in clinical isolates. Our data implies that the level of ergosterol contents determines the susceptibility to azoles and AmB in C. albicans. Deep understanding of the above mechanisms would offer new hope to treat drug-resistant C. albicans.
    Applied Microbiology and Biotechnology 01/2014; 98(6). DOI:10.1007/s00253-013-5425-5 · 3.34 Impact Factor
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