Study identifies mechanism underlying multidrug resistance in fungi

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Public release date: 2-Apr-2008

Study identifies mechanism underlying multidrug resistance in fungi

EurekAlert (press release) - Washington,DC*

Contact: Sue McGreevey

smcgreevey@...

617-724-2764

Massachusetts General Hospital

http://www.eurekalert.org/pub_releases/2008-04/mgh-sim033108.php

Finding could improve treatment of dangerous infections in immune-

compromised patients

A team of researchers led by Anders Näär, PhD, of the Massachusetts

General Hospital (MGH) Cancer Center has identified a mechanism

controlling multidrug resistance in fungi. This discovery could help

advance treatments for opportunistic fungal infections that

frequently plague individuals with compromised immunity, such as

patients receiving chemotherapy, transplant recipients treated with

immunosuppressive drugs, and AIDS patients. The findings appear in

the April 3 issue of Nature.

Almost 10 percent of bloodstream infections are caused by pathogenic

fungi, such as the Candida species; and the mortality of such

infections is approaching 40 percent. Just as many bacterial strains

have become resistant to important antibiotics, resistance to common

antifungal drugs is an increasing phenomenon in pathogenic fungi. To

better understand the molecular pathways controlling multidrug

resistance in fungi, the research team first investigated drug

resistance in baker's yeast, a common genetic model for observing

biological processes.

Using detailed genetic, biochemical, and molecular approaches, the

researchers found that yeast induce multidrug resistance via a

molecular switch similar to one that removes drugs and other foreign

substances from human cells. When the yeast protein Pdr1p binds to

antifungal drugs or other chemicals, it switches on molecular pumps

that remove the drugs from the cell. The research team showed that

this chemical switch also controls drug resistance in an important

human pathogenic fungus, Candida glabrata. In humans, a protein

called PXR is the drug sensor that turns on genes involved in

detoxifying and removing drugs from cells.

" This intriguing similarity between the regulatory switches

controlling multidrug resistance in fungi and drug detoxification in

humans will allow us to take advantage of the extensive knowledge of

the human molecular switch and identify new therapies for resistant

fungal infections in patients with compromised immunity, " says Näär,

an assistant professor of Cell Biology at Harvard Medical School

(HMS).

The researchers also found exactly how Pdr1p turns on the multidrug

resistance program. After binding to drugs, the Pdr1p protein

partners with another key mediator of genetic switches called

Gal11p. In-depth molecular and structural studies – in collaboration

with the team of co-author Gerhard Wagner, PhD, Elkan Blout

Professor of Biological Chemistry and Molecular Pharmacology at HMS –

identified the specific area of Gal11p that binds to Pdr1p to

induce multidrug resistance.

" This detailed understanding of the interaction between these

proteins will allow screening for small-molecule inhibitors of

protein binding. Such inhibitors may lead to novel co-therapeutics

that will sensitize multidrug-resistant fungal infections to

standard antifungal therapy, " says Wagner.

To further investigate the relevance of their findings, the

researchers used a C. elegans roundworm model system – recently

developed by co-author Eleftherios Mylonakis, MD, PhD, of MGH

Infectious Disease – to study fungal pathogens. They found that

worms infected with Candida glabrata that lacked either the Pdr1p or

Gal11p proteins could be successfully treated with typical

antifungal medications, suggesting that targeting the gene switch

controlled by those proteins' interaction could restore the

effectiveness of standard drugs.

" Fungal infections have a serious impact on immunocompromised

patients, and the development of resistance is particularly

worrisome, since targets for antifungal drugs are limited, " says

Mylonakis, an assistant professor of Medicine at HMS. " Given these

concerns, having the opportunity to use our model system for the in

vivo investigation of this resistance mechanism has been a

particularly fulfilling endeavor. "