Journal Article

A nuclear receptor-like pathway regulating multidrug resistance in fungi

Thakur, Jitendra K., Breger, Julia, Li, Darrick K., Cormack, Brendan P., Wagner, Gerhard, Struhl, Kevin, Näär, Anders M., Mylonakis, Eleftherios, Frueh, Dominique P., Gulshan, Kailash, Arthanari, Haribabu, Moye-Rowley, W. Scott, Pan, Shih-Jung, Fan, Xiaochun, Yang, Fajun

2008

Overview

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. Fungal drug resistance Multidrug resistance (MDR) is a serious complication during treatment of the opportunistic fungal infections that frequently afflict immunosupressed patients. MDR is often caused by upregulation of drug efflux pumps by members of the fungal zinc-cluster transcription-factor family (for example Pdr1p orthologues). Thakur et al . now show that Pdr1p-type molecules in the yeast Saccharomyces cerevisiae and the human pathogen Candida glabrata bind directly to structurally diverse drugs and toxic substances, resulting in stimulated expression of drug efflux pumps and induction of MDR. Improved knowledge of the molecular pathways controlling MDR in pathogenic fungi should facilitate the development of therapies to combat these intransigent infections. Fungal Pdr1p family proteins bind directly to diverse drugs and xenobiotics, resulting in activation of transcription and induction of multidrug resistance. The mechanism has analogy to regulation of multidrug resistance in vertebrates by nuclear receptors.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Action of physical and chemical agents / Animals / Antifungal Agents - metabolism / Antifungal Agents - pharmacology / Binding sites / Biological and medical sciences / Biomedical research / Candida glabrata / Candida glabrata - drug effects / Candida glabrata - genetics / Candida glabrata - metabolism / Chemotherapy / DNA-Binding Proteins - chemistry / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Drug resistance / Drug Resistance, Fungal - genetics / Fundamental and applied biological sciences. Psychology / Fungal infections / Fungal Proteins - chemistry / Fungal Proteins - genetics / Fungal Proteins - metabolism / Gene Expression Regulation, Fungal - genetics / Genes, Fungal - genetics / Humanities and Social Sciences / Mediator Complex / Metazoa / Microbiology / Molecular biology / multidisciplinary / Multigene Family / Mycology / Pathogens / Protein Structure, Tertiary / Pumps / Receptors, Steroid - metabolism / Saccharomyces cerevisiae / Saccharomyces cerevisiae - drug effects / Saccharomyces cerevisiae - genetics / Saccharomyces cerevisiae - metabolism / Saccharomyces cerevisiae Proteins - chemistry / Saccharomyces cerevisiae Proteins - genetics / Saccharomyces cerevisiae Proteins - metabolism / Science / Science (multidisciplinary) / Trans-Activators - chemistry / Trans-Activators - genetics / Trans-Activators - metabolism / Transcription Factors - metabolism / Transcription, Genetic - genetics / Vertebrates / Xenobiotics / Xenobiotics - metabolism