Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Potent, puzzling and (now less) toxic: Team discovers how antifungal drug works

16.04.2014

Scientists have solved a decades-old medical mystery – and in the process have found a potentially less toxic way to fight invasive fungal infections, which kill about 1.5 million people a year.

The researchers say they now understand the mechanism of action of amphotericin, an antifungal drug that has been in use for more than 50 years – even though it is nearly as toxic to human cells as it is to the microbes it attacks.


Photo by L. Brian Stauffer

A new collaboration solved a decades-old medical mystery involving an antifungal agent. Pictured, from left: graduate student Grant Hisao; chemistry professor Martin Burke; graduate students Alex Cioffi, Katrina Diaz, Marcus Tuttle and Mary Clay; chemistry professor Chad Rienstra; and graduate students Brice Uno, Tom Anderson and Matt Endo.

A report of the new findings appears in Nature Chemical Biology.

“Invasive fungal infections are a very important unmet medical need,” said University of Illinois and Howard Hughes Medical Institute chemistry professor Martin Burke, who led the study with chemistry professor Chad Rienstra. “There are about 3 million cases per year and what’s striking is that, even in 2014, half the patients who come into the hospital with an invasive fungal infection in their blood die.”

More people are killed by invasive fungal infections than by malaria or tuberculosis, Burke said.

Amphotericin (am-foe-TEHR-ih-sin) is the most effective broad-spectrum antifungal drug available, Burke said. But its use is limited by its toxicity to human cells.

“When I was a medical student, they used to call it ‘amphoterrible’ in the clinic because it has very powerful side effects,” he said. “And so you’re stuck between having the fungus kill the patient, versus using too much amphotericin, which kills the patient.”

Scientists have long sought to make amphotericin less toxic, but have been hindered by an obvious problem: Because it is so hard to study, no one knew exactly how it worked.

“This molecule is one of the most challenging to work with because it has a very complex structure, is poorly soluble and is sensitive to light, oxygen and acid,” Burke said.

Amphotericin also interacts with membranes, which are notoriously difficult to study. Many labs, including Burke’s, have tried to figure out the three-dimensional structure of amphotericin by crystallizing it, a standard technique. So far, all attempts have failed.

So the team turned to one of the most powerful tools for studying non-crystalline samples: solid-state nuclear magnetic resonance (NMR) spectroscopy, which measures how atomic nuclei respond to changes in a magnetic field.

“NMR is a great technique for detecting signals and interpreting the structural properties of molecules in solution,” said Rienstra, who led the NMR work with graduate students Mary Clay and Tom Anderson. But few labs use it to track interactions between small molecules in membranes, he said. “We developed several new NMR experiments to study amphotericin in the presence of membranes.”

Previous studies had found evidence that amphotericin opens up ion channels in membranes, perhaps making them more leaky to charged atoms that could disrupt a cell. Most scientists assumed that this was the drug’s main mode of action.

But the evidence also suggested that amphotericin interacted with sterols, such as cholesterol in animal cells and ergosterol in yeast. Rienstra and Burke focused on amphotericin’s influence on sterols, hypothesizing that this might be a key to its toxicity.

The initial NMR data supported this idea, indicating that very little of the drug – less than 5 percent – actually formed channels in membranes. Using NMR and other experimental tools, the Rienstra/Burke team found that most of the amphotericin aggregates on the exterior of membranes, extracting sterols out of membranes like a sponge. Cell death follows soon after.

 “For over 50 years, the mechanism by which amphotericin kills cells has remained a mystery,” Burke said. “But we are finally seeing the fog start to clear. This new understanding allows us to focus on how to make this molecule less toxic to human cells.”

In a separate study published in the Journal of the American Chemical Society, Burke and his colleagues appear to have accomplished just that. They developed a derivative of amphotericin that, at least in cell culture, binds to ergosterol in yeast but not to human cholesterol.

“We are very excited about this discovery,” Burke said. “But a great deal of work lies ahead to see if this compound has the potential to serve as a less toxic treatment for fungal infections in human patients. At this point, we just have a very promising compound. Most importantly, thanks to the collaboration between these two labs, we now know where to look for solutions to this longstanding problem.”

Preclinical trials of the new compound have begun, the researchers said.

The National Institutes of Health and the Howard Hughes Medical Institute supported portions of this work.

Diana Yates | University of Illinois at Urbana-Champaign
Further information:
http://news.illinois.edu/news/14/0415antifungal_MartinBurke_ChadRienstra.html

Further reports about: NMR Rienstra antifungal cholesterol fungal infections structure toxic toxicity

More articles from Life Sciences:

nachricht Researchers identify potentially druggable mutant p53 proteins that promote cancer growth
09.12.2016 | Cold Spring Harbor Laboratory

nachricht Plant-based substance boosts eyelash growth
09.12.2016 | Fraunhofer-Institut für Angewandte Polymerforschung IAP

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Electron highway inside crystal

Physicists of the University of Würzburg have made an astonishing discovery in a specific type of topological insulators. The effect is due to the structure of the materials used. The researchers have now published their work in the journal Science.

Topological insulators are currently the hot topic in physics according to the newspaper Neue Zürcher Zeitung. Only a few weeks ago, their importance was...

Im Focus: Significantly more productivity in USP lasers

In recent years, lasers with ultrashort pulses (USP) down to the femtosecond range have become established on an industrial scale. They could advance some applications with the much-lauded “cold ablation” – if that meant they would then achieve more throughput. A new generation of process engineering that will address this issue in particular will be discussed at the “4th UKP Workshop – Ultrafast Laser Technology” in April 2017.

Even back in the 1990s, scientists were comparing materials processing with nanosecond, picosecond and femtosesecond pulses. The result was surprising:...

Im Focus: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

Researchers identify potentially druggable mutant p53 proteins that promote cancer growth

09.12.2016 | Life Sciences

Scientists produce a new roadmap for guiding development & conservation in the Amazon

09.12.2016 | Ecology, The Environment and Conservation

Satellites, airport visibility readings shed light on troops' exposure to air pollution

09.12.2016 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>