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!
Proteomics and precision medicine
08.02.2016 | University of Iowa Health Care
Atomic clock experts from the Physikalisch-Technische Bundesanstalt (PTB) are the first research group in the world to have built an optical single-ion clock which attains an accuracy which had only been predicted theoretically so far. Their optical ytterbium clock achieved a relative systematic measurement uncertainty of 3 E-18. The results have been published in the current issue of the scientific journal "Physical Review Letters".
Atomic clock experts from the Physikalisch-Technische Bundesanstalt (PTB) are the first research group in the world to have built an optical single-ion clock...
The University of Würzburg has two new space projects in the pipeline which are concerned with the observation of planets and autonomous fault correction aboard satellites. The German Federal Ministry of Economic Affairs and Energy funds the projects with around 1.6 million euros.
Detecting tornadoes that sweep across Mars. Discovering meteors that fall to Earth. Investigating strange lightning that flashes from Earth's atmosphere into...
Physicists from Saarland University and the ESPCI in Paris have shown how liquids on solid surfaces can be made to slide over the surface a bit like a bobsleigh on ice. The key is to apply a coating at the boundary between the liquid and the surface that induces the liquid to slip. This results in an increase in the average flow velocity of the liquid and its throughput. This was demonstrated by studying the behaviour of droplets on surfaces with different coatings as they evolved into the equilibrium state. The results could prove useful in optimizing industrial processes, such as the extrusion of plastics.
The study has been published in the respected academic journal PNAS (Proceedings of the National Academy of Sciences of the United States of America).
Exceeding critical temperature limits in the Southern Ocean may cause the collapse of ice sheets and a sharp rise in sea levels
A future warming of the Southern Ocean caused by rising greenhouse gas concentrations in the atmosphere may severely disrupt the stability of the West...
Indications of light-induced lossless electricity transmission in fullerenes contribute to the search for superconducting materials for practical applications.
Superconductors have long been confined to niche applications, due to the fact that the highest temperature at which even the best of these materials becomes...
09.02.2016 | Event News
02.02.2016 | Event News
26.01.2016 | Event News
10.02.2016 | Life Sciences
10.02.2016 | Earth Sciences
10.02.2016 | Physics and Astronomy