ABC transporters coupled with the elevated ergosterol contents contribute to the azole resistance and amphotericin B susceptibility

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• 作者：Biao Ren (1) (2)
  Huan-Qin Dai (1)
  Gang Pei (1) (2) (3)
  Yao-Jun Tong (1) (2)
  Ying Zhuo (1)
  Na Yang (1) (2)
  Meng-Yi Su (1)
  Pei Huang (1) (2)
  Yu-Zhuo Yang (1)
  Li-Xin Zhang (1)
  
• 关键词：Drug resistance ; Amphotericin B ; Ergosterol ; Azoles ; Fluphenazine
• 刊名：Applied Microbiology and Biotechnology
• 出版年：2014
• 出版时间：March 2014
• 年：2014
• 卷：98
• 期：6
• 页码：2609-2616
• 全文大小：369 KB
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• 作者单位：Biao Ren (1) (2)
  Huan-Qin Dai (1)
  Gang Pei (1) (2) (3)
  Yao-Jun Tong (1) (2)
  Ying Zhuo (1)
  Na Yang (1) (2)
  Meng-Yi Su (1)
  Pei Huang (1) (2)
  Yu-Zhuo Yang (1)
  Li-Xin Zhang (1)
  
  1. Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100190, China
  2. University of Chinese Academy of Sciences, Beijing, 100049, China
  3. Helmholtz Centre for Infection Research, Braunschweig, Germany
  
• ISSN：1432-0614

文摘

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.