Article

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: 3.53). 06/2010; 5(6):e11309. DOI: 10.1371/journal.pone.0011309
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Lars M Steinmetz, May 29, 2014
0 Followers
 · 
162 Views
  • Source
    [Show abstract] [Hide abstract]
    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 · 12.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 · 3.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A subset of the family of ATP-binding cassette (ABC) transporters has been in focus owing to their involvement in conferring multidrug resistance in cancer cells and among immune compromised individuals. Saccharomyces cerevisiae is protected against xenobiotics by similar machineries that are part of the pleitropic drug resistance (PDR) network. The ABC transporter Pdr5 is an important member of this PDR network in yeast and is involved in cellular detoxification by the efflux of a wide variety of drugs and substrates. In this review, we focus on the aspects of detergent effects and the degeneracy in conserved sequences that is observed in the nucleotide binding domains of Pdr5 and discuss their functional relevance.
    Biological Chemistry 01/2011; 392(1-2):53-60. DOI:10.1515/BC.2011.011 · 2.69 Impact Factor