Featured Research

from universities, journals, and other organizations

Duke Researchers Identify The Mechanisms By Which Drug Combinations Kill Fungal Infections

Date:
February 12, 2002
Source:
Duke University Medical Center
Summary:
Molecular biologists in the Mycology Research Unit at Duke University Medical Center have traced cellular pathways that are targeted to enhance the action of drugs used to treat fungal infections in people with compromised immune systems, such as those undergoing organ and bone marrow transplants. The discovery of how the immune-suppressing drugs enhance the action of antifungal drugs could lead to the development of new drugs designed to treat fungal infections such as systemic yeast infections and often-deadly cryptococcal infections.

DURHAM, N.C. – Molecular biologists in the Mycology Research Unit at Duke University Medical Center have traced cellular pathways that are targeted to enhance the action of drugs used to treat fungal infections in people with compromised immune systems, such as those undergoing organ and bone marrow transplants. The discovery of how the immune-suppressing drugs enhance the action of antifungal drugs could lead to the development of new drugs designed to treat fungal infections such as systemic yeast infections and often-deadly cryptococcal infections.

Related Articles


Led by Dr. Joseph Heitman, who is a Howard Hughes Medical Institute investigator at Duke, the research team explored the mechanism behind the effectiveness of administering the azole class of antifungal drugs such as fluconazole (Diflucanβ), with cyclosporin or FK506, two drugs commonly used to suppress rejection of transplanted organs and tissues.

The study is published in the Feb. 15 issue of the EMBO Journal, a journal published by the European Molecular Biology Organization.

Cyclosporin and FK506 block rejection of transplanted organs by inhibiting immune-system signaling pathways that activate T-cells. These drugs block calcineurin, an enzyme that plays a critical role in activating immune cells. Suppression of the immune system is necessary for transplanted organs to survive, but renders patients susceptible to infections by bacteria, viruses and fungi.

"The azoles are very nontoxic in humans, but the problem is they don't kill fungal cells. Instead, these drugs act by inhibiting fungal cell growth. The cells stop growing, but they don't die. As a result, a lot of fungal isolates become resistant to the azoles," Heitman said.

The study was funded by grants from the National Institute of Allergy and Infectious Diseases.

Unlike bacteria or viruses, fungi are eukaryotic cells that resemble cells of the human body. Fungal infections can thus be difficult to treat, Heitman said. The majority of transplant recipients suffer one or more infections and these infections are a significant cause of morbidity and mortality. Cryptococcal infections occur to two to three out of every 100 transplant recipients and is associated with a 50 percent mortality rate. Candida albicans, which can cause thrush, esophagitis or vaginitis, is the most common fungal infection and is common in hospital settings.

Heitman said these findings open the door to the clinical use of drug combinations and could lead to the identification of additional drug targets.

"There's an ongoing need to develop better antifungal drugs. There is an increasing population of people who are at risk and some infections prove very difficult to treat," Heitman said.

"There are relatively few drugs to treat these infections, some have serious side effects, and drug resistant isolates have emerged. For some fungal infections, such as aspergillus infections in the lungs and cryptococcal infections in the brain, there is a 50 percent risk of death. These studies reveal new ways in which existing drugs can be combined to combat fungal infections and improve therapy," he said.

Combining fluconazole with either cyclosporin or FK506 was previously found by other researchers to potently kill fungal cells in the test tube, and had been proposed as an approach to combat difficult to treat fungal infections.

The multi-drug antifungal treatment concept was tested in mice in 2000 by a research team led by Dominque Sanglard, an investigator at the CHUV Hospital in Lausanne, Switerzerland, and an international scholar of the Howard Hughes Medical Institute. Their studies demonstrated that the combination of cyclosporin and fluconazole successfully eradicated fungal infections, but the cellular targets and the mechanism of drug action were not understood. Elucidating the molecular targets could open the door for new or improved drugs, Heitman said.

"The big question was, ‘What are the molecules that cyclosporin and FK506 target to allow the azole drugs to kill the fungal cell?' One previous proposal was that cyclosporin inhibits the pumps that extrude the fluconazole drug from the cell. We found that this is not the mechanism of action. Instead, both cyclosporin and FK506 enter the fungal cell and inhibit calcineurin, which is their well-established target.

"We discovered that calcineurin is a component of a fungal stress response that allows the cell to survive assault on the membrane by the azoles. Inhibition of calcineurin cripples this stress response and now allows the azoles to kill rather than simply maim the fungal cells," he said.

The researchers at Duke, which also included Maria Elena Cardenas and John McCusker from the departments of genetics and microbiology, and Dr. John Perfect from the department of medicine, used molecular genetic approaches to pinpoint calcineurin as the target of the synergistic drug dynamic duo.

When a mutation was introduced into calcineurin that prevents binding to FK506, this conferred resistance to the drug combination. They also made loss of function mutations in which they removed calcineurin from the cell. The cells were viable, but they now died when exposed to azole drugs that fail to kill wild-type cells. Thus, these studies reveal new ways in which existing drugs can be combined to combat fungal infections and improve therapy.


Story Source:

The above story is based on materials provided by Duke University Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

Duke University Medical Center. "Duke Researchers Identify The Mechanisms By Which Drug Combinations Kill Fungal Infections." ScienceDaily. ScienceDaily, 12 February 2002. <www.sciencedaily.com/releases/2002/02/020207075321.htm>.
Duke University Medical Center. (2002, February 12). Duke Researchers Identify The Mechanisms By Which Drug Combinations Kill Fungal Infections. ScienceDaily. Retrieved October 23, 2014 from www.sciencedaily.com/releases/2002/02/020207075321.htm
Duke University Medical Center. "Duke Researchers Identify The Mechanisms By Which Drug Combinations Kill Fungal Infections." ScienceDaily. www.sciencedaily.com/releases/2002/02/020207075321.htm (accessed October 23, 2014).

Share This



More Plants & Animals News

Thursday, October 23, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Black Bear Cub Goes Sunday Shopping

Black Bear Cub Goes Sunday Shopping

Reuters - Light News Video Online (Oct. 23, 2014) — Price check on honey? Bear cub startles Oregon drugstore shoppers. Rough Cut (no reporter narration). Video provided by Reuters
Powered by NewsLook.com
Dances With Wolves in China's Wild West

Dances With Wolves in China's Wild West

AFP (Oct. 23, 2014) — One man is on a mission to boost the population of wolves in China's violence-wracked far west. The animal - symbol of the Uighur minority there - is under threat with a massive human resettlement program in the region. Duration: 00:41 Video provided by AFP
Powered by NewsLook.com
Working Mother DIY: Pumpkin Pom-Pom

Working Mother DIY: Pumpkin Pom-Pom

Working Mother (Oct. 22, 2014) — How to make a pumpkin pom-pom. Video provided by Working Mother
Powered by NewsLook.com
Goofy Dinosaur Blends Barney and Jar Jar Binks

Goofy Dinosaur Blends Barney and Jar Jar Binks

AP (Oct. 22, 2014) — A collection of dinosaur bones reveal a creature that is far more weird and goofy-looking than scientists originally thought when they found just the arm bones nearly 50 years ago, according to a new report in the journal Nature. (Oct. 22) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

Strange & Offbeat Stories

 

Plants & Animals

Earth & Climate

Fossils & Ruins

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins