Navigation Links
Study identifies mechanism underlying multidrug resistance in fungi

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
Massachusetts General Hospital

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:
(Date:11/27/2015)... ... 2015 , ... Lizzie’s Lice Pickers just announced a special promotion that will ... their purchase of lice treatment product. In addition, customers will receive a complimentary head ... “Finding lice is a sure way to ruin the holidays, so we encourage all ...
(Date:11/27/2015)... ... November 27, 2015 , ... Consistent with ... the 2016 Building Better Radiology Marketing Programs meeting will showcase some ... March 6, 2016, at Caesars Palace in Las Vegas with a pre-conference session ...
(Date:11/27/2015)... Bangalore, Karnataka (PRWEB) , ... November 27, 2015 ... ... the world, Health-E-minds, an innovative online platform for mental health and wellness consultation, ... KleverKid. , This partnership will bridge the knowledge gap experienced by parents and ...
(Date:11/27/2015)... ... November 27, 2015 , ... Avid collector, Andrew Hawley from ... boxing style concert posters. This is one of Joplin's most famous and beautiful concert ... the University of Michigan in Ann Arbor. The According to Hawley, "It is hard ...
(Date:11/26/2015)... ON and Cambridge, ON (PRWEB) , ... November ... ... today the availability of a real-time eReferral system for diagnostic imaging in the ... ultrasounds, X-rays, mammography, BMD and Nuclear Medicine tests directly from their electronic medical ...
Breaking Medicine News(10 mins):
(Date:11/26/2015)... --> ... att använda SyMRI för att hitta optimal ... med multipel skleros (MS) eller hjärntumörmetastaser och ... för att kunna använda SyMRI Research Edition ... kan man generera flera konstrastbilder från en ...
(Date:11/26/2015)... , November 26, 2015 /PRNewswire/ ... announced the addition of the  "2016 ... the European Therapeutic Drug Monitoring (TDM) ... Competitive Intelligence, Emerging Opportunities"  report to ... ) has announced the addition of ...
(Date:11/26/2015)... ) has announced ... High Viscosity Drugs" report to their offering. ... addition of the "Self Administration of High ... --> Research and Markets ( ) ... Administration of High Viscosity Drugs" report to ...
Breaking Medicine Technology: