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Study identifies mechanism underlying
multidrug resistance in fungi
Finding could improve treatment
of dangerous infections in immune-compromised patients
BOSTON - April 2, 2008 - 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."
The study was supported by grants from the National Institutes
of Health and the MGH Fund for Medical Discovery. The co-first authors
of the Nature report are Jitendra Thakur, PhD, and Fajun
Yang, PhD, of the MGH Cancer Center and Haribabu Arthanari, PhD,
HMS Biological Chemistry and Molecular Pharmacology. Additional
co-authors are Julia Breger and Darrick Li, MGH; Xiaochun Fan, PhD,
Dominique Frueh, PhD, and Kevin Struhl, PhD, HMS; Shih-Jung Pan
and Brendan Cormack, PhD, Johns Hopkins School of Medicine; and
Kailash Gulshan and Scott Moye-Rowley, PhD, University of Iowa.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $500 million
and major research centers in AIDS, cardiovascular research, cancer,
computational and integrative biology, cutaneous biology, human
genetics, medical imaging, neurodegenerative disorders, regenerative
medicine, systems biology, transplantation biology and photomedicine.
Media Contacts: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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