Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Powerful drug's surprising, simple method could lead to better treatments

17.01.2012
With one simple experiment, University of Illinois chemists have debunked a widely held misconception about an often-prescribed drug.

Led by chemistry professor and Howard Hughes Medical Institute early career scientist Martin Burke, the researchers demonstrated that the top drug for treating systemic fungal infections works by simply binding to a lipid molecule essential to yeast’s physiology, a finding that could change the direction of drug development endeavors and could lead to better treatment not only for microbial infections but also for diseases caused by ion channel deficiencies.

“Dr. Burke’s elegant approach to synthesizing amphotericin B, which has been used extensively as an antifungal for more than 50 years, has now allowed him to expose its elusive mode of action,” said Miles Fabian, who oversees medicinal chemistry research at the National Institute of General Medical Sciences. The institute is part of the National Institutes of Health, which supported the work. “This work opens up avenues for improving upon current antifungals and developing novel approaches for the discovery of new agents.”

Systemic fungal infections are a problem worldwide and affect patients whose immune systems have been compromised, such as the elderly, patients treated with chemotherapy or dialysis, and those with HIV or other immune disorders. A drug called amphotericin (pronounced AM-foe-TARE-uh-sin) has been medicine’s best defense against fungal infections since its discovery in the 1950s. It effectively kills a broad spectrum of pathogenic fungi and yeast, and has eluded the resistance that has dogged other antibiotics despite its long history of use.

The downside? Amphotericin is highly toxic.
“When I was in my medical rotations, we called it ‘ampho-terrible,’ because it’s an awful medicine for patients,” said Burke, who has an M.D. in addition to a Ph.D. “But its capacity to form ion channels is fascinating. So my group asked, could we make it a better drug by making a derivative that’s less toxic but still powerful? And what could it teach us about avoiding resistance in clinical medicine and possibly even replacing missing ion channels with small molecules? All of this depends upon understanding how it works, but up until now, it’s been very enigmatic.”

While amphotericin’s efficacy is clear, the reasons for its remarkable infection-fighting ability remained uncertain. Doctors and researchers do know that amphotericin creates ion channels that permeate the cell membrane. Physicians have long assumed that this was the mechanism that killed the infection, and possibly the patient’s cells as well. This widely accepted dogma appears in many scientific publications and textbooks.

However, several studies have shown that channel formation alone may not be the killing stroke. In fact, as Burke’s group discovered, the mechanism is much simpler.

Amphotericin binds to a lipid molecule called ergosterol, prevalent in fungus and yeast cells, as the first step in forming the complexes that make ion channels. But Burke’s group found that, to kill a cell, the drug doesn’t need to create ion channels at all – it simply needs to bind up the cell’s ergosterol.

Burke’s group produced a derivative of amphotericin using a molecule synthesis method Burke pioneered called iterative cross-coupling (ICC), a way of building designer molecules using simple chemical “building blocks” called MIDA boronates joined together by one simple reaction. They created a derivative that could bind ergosterol but could not form ion channels, and tested it against the original amphotericin.

If the widely accepted model was true, and ion channel formation was the drug’s primary antifungal action, then the derivative would not be able to wipe out a yeast colony. But the ergosterol-binding, non-channel-forming derivative was almost equally potent to natural amphotericin against both of the yeast cell lines the researchers tested, once of which is highly pathogenic in humans. The researchers detailed their findings in the journal Proceedings of the National Academy of Sciences.

“The results are all consistent with the same conclusion: In contrast to half a century of prior study and the textbook-classic model, amphotericin kills yeast by simply binding ergosterol,” Burke said.

“The beauty is, because we now know this is the key mechanism, we can focus squarely on that goal. Now we can start to think about drug discovery programs targeting lipid binding.”

The researchers currently are working to synthesize a derivative that will bind to ergosterol in yeast cells, but will not bind to cholesterol in human cells, to see if that could kill an infection without harming the patient. They also hope to explore other derivatives that would target lipids in fungi, bacteria and other microbes that are not present in human cells. Attacking these lipids could be a therapeutic strategy that may defy resistance.

In addition to exploiting amphotericin’s lipid-binding properties for antimicrobial drugs, Burke and his group hope to harness its channel-creating ability to develop treatments for conditions caused by ion-channel deficiencies; for example, cystic fibrosis. These new findings suggest that the ion-channel mechanism could be decoupled from the cell-killing mechanism, thus enabling development of derivatives that could serve as “molecular prosthetics,” replacing missing proteins in cell membranes with small-molecule surrogates.

“Now we have a road map to take ampho-terrible and turn it into ampho-terrific,” Burke said.

Editor’s notes: To reach Martin Burke, call (217)244-8726; email burke@scs.illinois.edu.

The paper, “Amphotericin Primarily Kills Yeast by Simply Binding Ergosterol,” is available from the News Bureau or PNAS.

Liz Ahlberg | University of Illinois
Further information:
http://www.illinois.edu

More articles from Life Sciences:

nachricht Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory

nachricht How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>