The findings, which could lead to new treatments for a disease that kills more HIV/AIDS patients than tuberculosis, appear in mBio®, the online open-access journal of the American Society for Microbiology (ASM.)
"This work sets the stage for additional animal studies to see if tamoxifen can be used as a drug in people and will allow us to design new drugs related to tamoxifen that are better antifungals," says Damian Krysan of the University of Rochester, an author on the study.
Cryptococcosis is one of the most prevalent human fungal infections, responsible for approximately 1 million new infections and 620,000 deaths worldwide each year. The disease strikes primarily people living with HIV/AIDS and causes more deaths in this population than tuberculosis. It manifests as either pneumonia or a brain infection known as meningoencephalitis.
"The gold standard therapy for this infection is a combination of amphotericin B and 5-flucytosine. These drugs were first used in the late 1950s when penicillin was the antibiotic of choice. There have been no substantial improvements in the treatment of this disease in a half-century and the therapy is not available in many regions of the world that need it most," says Krysan.
In areas of the world where the gold-standard therapy is not available, like sub-Saharan Africa, the drug of choice is fluconazole because it is widely available and inexpensive. Unfortunately, it is much less effective since it does not actually kill the fungus.
"Recently, interest in re-using old drugs to treat new diseases has increased as a way to develop new therapies more quickly. We screened a large collection of old drugs for drugs that kill Cryptococcus and rediscovered tamoxifen," says Krysan. "We used clinical microbiology tests to determine whether the molecules had promising activity against Cryptococcus both alone and in combination with other antifungal drugs such as fluconazole. The combination of tamoxifen and fluconazole was synergistic; this means that the combination is more than 4-times more active than either alone."
Krysan and his colleagues also demonstrated that tamoxifen does not kill the fungus in the same way it works against breast cancer. Instead, it inhibits proteins related to calmodulin, an important calcium binding protein. They found that by making modifications to tamoxifen that improve its ability to interfere with calmodulin, they also improved its ability to kill Cryptococcus.
"An effective, widely available treatment for cryptococcal meningitis is an unmet clinical need of global importance," says Krysan. "These results indicate that tamoxifen is a pharmacologically attractive scaffold for the development of new anti-cryptococcal drugs and provide a mechanistic base for its further optimization."
mBio® is an open access online journal published by the American Society for Microbiology to make microbiology research broadly accessible. The focus of the journal is on rapid publication of cutting-edge research spanning the entire spectrum of microbiology and related fields. It can be found online at http://mbio.asm.org.
The American Society for Microbiology is the largest single life science society, composed of over 39,000 scientists and health professionals. ASM's mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.
Jim Sliwa | EurekAlert!
Understanding the Body’s Response to Worms and Allergies
24.04.2015 | University of Manchester
Caring for blindness: A new protein in sight?
22.04.2015 | NSERM (Institut national de la santé et de la recherche médicale)
KAIST researchers published an article on the development of a novel technique to precisely track the 3-D positions of optically-trapped particles having complicated geometry in high speed in the April 2015 issue of Optica.
Daejeon, Republic of Korea, April 23, 2015--Optical tweezers have been used as an invaluable tool for exerting micro-scale force on microscopic particles and...
A very small and rare species of shark is swimming its way through scientific literature. But don't worry, the chances of this inches-long vertebrate biting...
Ever since computers have been small enough to be fixtures on desks and laps, their central processing has functioned something like an atomic Etch A Sketch, with electromagnetic fields pushing data bits into place to encode data.
Unfortunately, the same drawbacks and perils of the mechanical sketch board have been just as pervasive in computing: making a change often requires starting...
How is lightning initiated in thunderclouds? This is difficult to answer - how do you measure electric fields inside large, dangerously charged clouds? It was discovered, more or less by coincidence, that cosmic rays provide suitable probes to measure electric fields within thunderclouds. This surprising finding is published in Physical Review Letters on April 24th. The measurements were performed with the LOFAR radio telescope located in the Netherlands.
How is lightning initiated in thunderclouds? This is difficult to answer - how do you measure electric fields inside large, dangerously charged clouds? It was...
Max Planck researcher Buhalqem Mamtimin determines how much nitrogen oxide is released into the atmosphere from agriculturally used oases.
In order to make statements about current and future air pollution, scientists use models which simulate the Earth’s atmosphere. A lot of information such as...
23.04.2015 | Event News
23.04.2015 | Event News
13.04.2015 | Event News
27.04.2015 | Life Sciences
27.04.2015 | Power and Electrical Engineering
27.04.2015 | Life Sciences