Article

Nature 452, 604-609 (3 April 2008) | doi:10.1038/nature06836; Received 19 October 2007; Accepted 5 February 2008

A nuclear receptor-like pathway regulating multidrug resistance in fungi

Jitendra K. Thakur1,2,7, Haribabu Arthanari3,7, Fajun Yang1,2,7, Shih-Jung Pan4, Xiaochun Fan3, Julia Breger5, Dominique P. Frueh3, Kailash Gulshan6, Darrick K. Li1, Eleftherios Mylonakis5, Kevin Struhl3, W. Scott Moye-Rowley6, Brendan P. Cormack4, Gerhard Wagner3 & Anders M. Näär1,2

  1. Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA
  2. Department of Cell Biology,
  3. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
  4. Department of Molecular Biology and Genetics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA
  5. Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
  6. Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa 52242, USA
  7. These authors contributed equally to this work.

Correspondence to: Anders M. Näär1,2 Correspondence and requests for materials should be addressed to A.M.N. (Email: naar@helix.mgh.harvard.edu).

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Multidrug resistance (MDR) is a serious complication during treatment of opportunistic fungal infections that frequently afflict immunocompromised individuals, such as transplant recipients and cancer patients undergoing cytotoxic chemotherapy. Improved knowledge of the molecular pathways controlling MDR in pathogenic fungi should facilitate the development of novel therapies to combat these intransigent infections. MDR is often caused by upregulation of drug efflux pumps by members of the fungal zinc-cluster transcription-factor family (for example Pdr1p orthologues). However, the molecular mechanisms are poorly understood. Here we show that Pdr1p family members in Saccharomyces cerevisiae and the human pathogen Candida glabrata directly bind to structurally diverse drugs and xenobiotics, resulting in stimulated expression of drug efflux pumps and induction of MDR. Notably, this is mechanistically similar to regulation of MDR in vertebrates by the PXR nuclear receptor, revealing an unexpected functional analogy of fungal and metazoan regulators of MDR. We have also uncovered a critical and specific role of the Gal11p/MED15 subunit of the Mediator co-activator and its activator-targeted KIX domain in antifungal/xenobiotic-dependent regulation of MDR. This detailed mechanistic understanding of a fungal nuclear receptor-like gene regulatory pathway provides novel therapeutic targets for the treatment of multidrug-resistant fungal infections.

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