A nuclear receptor-like pathway regulating multidrug resistance in fungi

Jitendra K. Thakur, Haribabu Arthanari, Fajun Yang, Shih-Jung Pan, Xiaochun Fan, Julia Breger, Dominique P. Frueh, Kailash Gulshan, Darrick K. Li, Eleftherios Mylonakis, Kevin Struhl, W. Scott Moye-Rowley, Brendan P. Cormack, Gerhard Wagner and Anders M. Näär ()
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Jitendra K. Thakur: Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA
Haribabu Arthanari: Harvard Medical School, Boston, Massachusetts 02115, USA
Fajun Yang: Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA
Shih-Jung Pan: Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA
Xiaochun Fan: Harvard Medical School, Boston, Massachusetts 02115, USA
Julia Breger: Massachusetts General Hospital, Boston, Massachusetts 02114, USA
Dominique P. Frueh: Harvard Medical School, Boston, Massachusetts 02115, USA
Kailash Gulshan: University of Iowa, Iowa City, Iowa 52242, USA
Darrick K. Li: Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA
Eleftherios Mylonakis: Massachusetts General Hospital, Boston, Massachusetts 02114, USA
Kevin Struhl: Harvard Medical School, Boston, Massachusetts 02115, USA
W. Scott Moye-Rowley: University of Iowa, Iowa City, Iowa 52242, USA
Brendan P. Cormack: Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA
Gerhard Wagner: Harvard Medical School, Boston, Massachusetts 02115, USA
Anders M. Näär: Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA

Nature, 2008, vol. 452, issue 7187, 604-609

Abstract: Abstract 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.

Date: 2008
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DOI: 10.1038/nature06836

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