Navigation Links
Study identifies mechanism underlying multidrug resistance in fungi
Date:4/2/2008

A team of researchers led by Anders Nr, 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 bakers 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 Nr, 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.


'/>"/>

Contact: Sue McGreevey
smcgreevey@partners.org
617-724-2764
Massachusetts General Hospital
Source:Eurekalert

Related medicine news :

1. Overweight kids have fewer cavities, new study shows
2. Families of children with cancer support human tissue research, study finds
3. Study Finds Older Corneas Suitable for Transplantation
4. ExoSeal vascular plug gets good reviews in ECLIPSE study
5. Iso-osmolar X-ray dye falters in PCI study
6. SEISMIC study issues glum report on cell therapy
7. Dallas area cornea shortages could benefit from national study
8. Humans have more distinctive hearing than animals, Hebrew U study shows
9. Drug use increasingly glamorized in rap music, according to new study of 2-decade trends
10. New study finds glamorization of drugs in rap music jumped dramatically over 2 decades
11. Indiana University study finds majority of US physicians favor national health insurance
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:5/28/2016)... ... May 28, 2016 , ... SuperCloset is proud to officially ... the day to day issues, struggles and obstacles veterans’ need to overcome in order ... Project provides active or retired military veteran(s) with a donated SuperCloset product based on ...
(Date:5/27/2016)... ... 2016 , ... More than a third of American adults are considered obese, ... has received increased attention in recent years, as an article published May ... loss, most people are familiar with the basic requirements of maintaining a healthy diet ...
(Date:5/27/2016)... ... May 27, 2016 , ... With over 60 percent ... the demand for a sustainable product to aid in the rehabilitation process has steadily ... the recovery of individuals with hemiplegia due to stroke. , Ekso Bionics has now ...
(Date:5/27/2016)... (PRWEB) , ... May 27, 2016 , ... ... this installment is bolstered by inspiring human interest stories, courtesy of leaders in ... trends and tech within the industry, from leading advocates and associations—namely Jones & ...
(Date:5/26/2016)... , ... May 26, 2016 , ... There are many ... Dog and Sausage Council (NHDSC) suggests that Americans prefer their dogs straight off the ... percent say grilling is their favorite way to cook a hot dog, far outpacing ...
Breaking Medicine News(10 mins):
(Date:5/24/2016)...   , Study met both ... superiority in , Excellent plus Good ... of the ascending colon   , ... today announced new positive data from the phase III MORA study ... 2 litre PEG with ascorbate. The study met both primary endpoints ...
(Date:5/24/2016)...  NxStage Medical, Inc. (Nasdaq: NXTM ), ... care, today announced that Jeffrey H. Burbank , ... schedule of investor conferences. Where applicable, a webcast of ... .   ... Friday, June 10, 2016 1:30 p.m. ET ...
(Date:5/24/2016)... HONG KONG , May 24, 2016 ... , the world , s ... and AV fistula intervention   OrbusNeich, a ... solutions, has expanded its portfolio to include products to ... balloons are the company,s first entry devices for lower ...
Breaking Medicine Technology: