Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Molecular doorstop could be key to new tuberculosis drugs

20.03.2018

Tuberculosis, which infects roughly one quarter of the world's population and kills nearly two million people a year, is not only deadly but ancient: signs of the disease have been found in Egyptian mummies. Despite its age, Mycobacterium tuberculosis, the pathogen that causes the illness, continues to learn new tricks. It has a particular knack for evolving antibiotic resistance, leaving hundreds of thousands of people with few treatment options.

Now, research conducted by Rockefeller scientists under the direction of Seth Darst, the Jack Fishman Professor, and Elizabeth Campbell, a senior research associate in Darst's laboratory, offers hope for a new and potent weapon against tuberculosis.


RNA polymerase, an enzyme essential to life, uses a specialized clamp to latch onto DNA.

Credit: Laboratory of Molecular Biophysics at The Rockefeller University

Usage Restrictions: Image may be used only to illustrate the research described in the accompanying release.

Their work, which appears in eLife, focuses on an antibiotic that kills M. tuberculosis in the laboratory, but is not suitable for clinical use. By explaining how the drug operates, their research might allow others to design new antibiotics that could in fact be used to treat tuberculosis patients--and might even work on other bugs.

A flawed candidate

Campbell explains that the antibiotic in question, fidaxomicin, is uncommonly adept at killing M. tuberculosis cultivated in the lab. To be useful against tuberculosis in the real world, however, an antibiotic must be absorbed by the gut and eventually reach the lungs when taken orally--something that fidaxomicin cannot do.

Fidaxomicin targets an enzyme called RNA polymerase (RNAP), which transcribes DNA into RNA, a process fundamental to life. The enzyme possesses a hinged pincer, or clamp, that swings shut to secure DNA for transcription.

Scientists suspected that the drug works by somehow interfering with this clamp. But they didn't know precisely how the molecule went about its job--knowledge that would be essential to creating more useful versions of fidaxomicin.

By using a powerful imaging technique known as cryo-electron microscopy, however, Campbell and her colleagues were able to figure out exactly how the antibiotic throws a wrench into RNAP.

Open wide

Thanks to earlier research, the team already knew that the version of the enzyme found in M. tuberculosis only works properly when combined with a protein called RbpA--a transcription factor not found in all bacteria. RbpA winds itself into a narrow pocket located at the base of the RNAP clamp, making it fully functional. Using cryo-EM, post-doctoral fellow Hande Boyaci and graduate student James Chen were able to show for the first time that fidaxomicin binds to RbpA as well as other parts of the RNAP deep inside that pocket.

What's more, they were able to pinpoint what happens when the two molecules come together: fidaxomicin physically jams the enzyme's clamp open and won't allow it to close.

"It acts like a doorstop, and prevents the clamp from securing DNA for transcription," says Campbell.

Endless possibilities

Next, Campbell and her associates went a step further. Working with a non-pathogenic cousin of M. tuberculosis called M. smegmatis, the team used a mutant form of the bacteria that lacked the part of RbpA that interacts with fidaxomicin. When exposed to fidaxomicin, normal Mycobacteria could not grow. The mutants, however, were able to thrive despite the presence of the antibiotic and went about multiplying as usual, confirming what the researchers already suspected: that RbpA is an essential part of the mechanism that makes these microbes vulnerable to the drug.

Medicinal chemists might be able to use this insight into how fidaxomicin works to design versions of the antibiotic that are absorbed through the gut, or to identify other drugs that also bind in the RNAP pocket and interact with RpbA. Antibiotics that require RbpA to work would be very useful since they would kill only the select group of bacteria that contain RbpA. Antibiotics that kill indiscriminately can cause significant collateral damage, wiping out benevolent bacteria and breeding resistance among more dangerous ones.

At the same time, because all bacterial RNAP possesses the same pocket that fidaxomicin uses as its binding site, drug developers might also be able to use the team's structural data to develop antibiotics that kill bugs that do not rely upon RbpA at all.

"Our hope is that drug companies will use these studies as a platform for modifying and designing antimicrobials," says Campbell. "They could use the structures we analyzed to design antibiotics that would only inhibit Mycobacteria, but they could probably also design broad-spectrum antibiotics that would kill a wide range of other bacteria."

Media Contact

Katherine Fenz
kfenz@rockefeller.edu
212-327-7913

 @rockefelleruniv

http://www.rockefeller.edu 

Katherine Fenz | EurekAlert!

More articles from Life Sciences:

nachricht Too much of a good thing: overactive immune cells trigger inflammation
16.09.2019 | Universität Basel

nachricht The sleep neuron in threadworms is also a stop neuron
16.09.2019 | Goethe-Universität Frankfurt am Main

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Tomorrow´s coolants of choice

Scientists assess the potential of magnetic-cooling materials

Later during this century, around 2060, a paradigm shift in global energy consumption is expected: we will spend more energy for cooling than for heating....

Im Focus: The working of a molecular string phone

Researchers from the Department of Atomically Resolved Dynamics of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg, the University of Potsdam (both in Germany) and the University of Toronto (Canada) have pieced together a detailed time-lapse movie revealing all the major steps during the catalytic cycle of an enzyme. Surprisingly, the communication between the protein units is accomplished via a water-network akin to a string telephone. This communication is aligned with a ‘breathing’ motion, that is the expansion and contraction of the protein.

This time-lapse sequence of structures reveals dynamic motions as a fundamental element in the molecular foundations of biology.

Im Focus: Milestones on the Way to the Nuclear Clock

Two research teams have succeeded simultaneously in measuring the long-sought Thorium nuclear transition, which enables extremely precise nuclear clocks. TU Wien (Vienna) is part of both teams.

If you want to build the most accurate clock in the world, you need something that "ticks" very fast and extremely precise. In an atomic clock, electrons are...

Im Focus: Graphene sets the stage for the next generation of THz astronomy detectors

Researchers from Chalmers University of Technology have demonstrated a detector made from graphene that could revolutionize the sensors used in next-generation space telescopes. The findings were recently published in the scientific journal Nature Astronomy.

Beyond superconductors, there are few materials that can fulfill the requirements needed for making ultra-sensitive and fast terahertz (THz) detectors for...

Im Focus: Physicists from Stuttgart prove the existence of a supersolid state of matte

A supersolid is a state of matter that can be described in simplified terms as being solid and liquid at the same time. In recent years, extensive efforts have been devoted to the detection of this exotic quantum matter. A research team led by Tilman Pfau and Tim Langen at the 5th Institute of Physics of the University of Stuttgart has succeeded in proving experimentally that the long-sought supersolid state of matter exists. The researchers report their results in Nature magazine.

In our everyday lives, we are familiar with matter existing in three different states: solid, liquid, or gas. However, if matter is cooled down to extremely...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Society 5.0: putting humans at the heart of digitalisation

10.09.2019 | Event News

Interspeech 2019 conference: Alexa and Siri in Graz

04.09.2019 | Event News

AI for Laser Technology Conference: optimizing the use of lasers with artificial intelligence

29.08.2019 | Event News

 
Latest News

Too much of a good thing: overactive immune cells trigger inflammation

16.09.2019 | Life Sciences

Scientists create a nanomaterial that is both twisted and untwisted at the same time

16.09.2019 | Materials Sciences

Researchers have identified areas of the retina that change in mild Alzheimer's disease

16.09.2019 | Health and Medicine

VideoLinks
Science & Research
Overview of more VideoLinks >>>