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!
PET imaging tracks Zika virus infection, disease progression in mouse model
20.09.2017 | US Army Medical Research Institute of Infectious Diseases
'Exciting' discovery on path to develop new type of vaccine to treat global viruses
18.09.2017 | University of Southampton
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.
Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems Holding GmbH about commercial use of a multi-well tissue plate for automated and reliable tissue engineering & drug testing.
MBM ScienceBridge GmbH successfully negotiated a license agreement between University Medical Center Göttingen (UMG) and the biotech company Tissue Systems...
Pathogenic bacteria are becoming resistant to common antibiotics to an ever increasing degree. One of the most difficult germs is Pseudomonas aeruginosa, a...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
20.09.2017 | Life Sciences
20.09.2017 | Power and Electrical Engineering
20.09.2017 | Physics and Astronomy