Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Atomic-scale view of bacterial proteins offers path to new tuberculosis drugs

06.02.2017

With the first detailed analysis of a cellular component from a close relative of the pathogen that causes tuberculosis, Rockefeller scientists are suggesting strategies for new drugs to curb this growing health problem. Each year, nearly half a million people around the world are infected with mutant TB strains capable of evading existing antibiotics.

The research, conducted by a Rockefeller team led by Elizabeth Campbell, in collaboration with scientists at Memorial Sloan Kettering, focuses on a cluster of interacting proteins called RNA polymerase. Crucial to all cells, this protein machine carries out a fundamental process in which genes within the DNA blueprint are copied into RNA. The RNA polymerase is the target of the antibiotic rifampicin--a lynchpin of modern TB treatment, which relies on a combination of drugs. Some bacteria become resistant to rifampicin by acquiring RNA polymerase mutations.


This detailed, 3-D map of a cluster of bacterial proteins is yielding new ideas for how to combat multi-resistant tuberculosis.

Credit: Laboratory of Molecular Biophysics at the Rockefeller University/eLife

"Now that we can visualize the molecular machinery of the bacteria that the drug targets, we can use a structure-guided approach to better understand how the drug works, how bacteria become resistant to it, and how to potentially improve the drug's action," says Campbell, a senior research associate in Seth Darst's Laboratory of Molecular Biophysics. She is one of the senior authors of a report published in the online journal eLife.

A molecular map

To visualize the structure the researchers used an imaging method known as x-ray crystallography. By crystalizing enzymes and other molecules interacting with each other--essentially freezing them in action--investigators are able to see how they fit together, much like keys fitting into locks. This ability to visualize what's going on can point the way toward more effective drugs, which may be able to latch more securely onto enzymes and other molecules.

"Based on the findings reported in this study," Campbell says, "we're already investigating new compounds with new mechanisms of action that appear to inhibit the rifampicin-resistant version of TB. Our eventual goal is to get them into clinical trials investigating new treatments for TB, including rifampicin-resistant TB."

Rockefeller chemist Sean Brady, who was not directly involved in the study, provided the team with these new compounds. He is now working together with Campbell, Darst, and other colleagues to further develop them into antibiotics and characterize the basis of their activity.

Not all bacteria are alike

It's estimated that up to one-third of the world's population is infected with M. tuberculosis, the bacterium that causes TB. In the study, the researchers worked with a closely related strain called M. smegmatis. "We needed hundreds of liters of cells to get enough of the material to do the crystallization," says Elizabeth Hubin, a former Rockefeller graduate student who carried out much of the work. "M. tuberculosis grows too slowly to be able to collect the volume that's needed, and it's very dangerous to work with in the lab."

But M. smegmatis relies on an RNA polymerase that is almost identical in sequence, structure, and behavior to the M. tuberculosis RNA polymerase, which led to another important finding in the study: The RNA polymerase from Escherichia coli, the bacterium most commonly used in lab research, is not. This means there may be a drawback to relying on E. coli as a model when developing certain types of antibiotics for bacteria that cause TB or other diseases.

"Most of the studies previously done with RNA polymerase were done using E. coli," Campbell says. "We've always assumed that the enzyme works the same way in all bacteria, but our study shows we can't assume what's found in one bacteria applies to all bacteria.

"Every pathogen needs to be studied individually," she adds, "so the field has a lot of work to do."

Media Contact

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

 @rockefelleruniv

http://www.rockefeller.edu 

Katherine Fenz | EurekAlert!

More articles from Health and Medicine:

nachricht Chronic stress induces fatal organ dysfunctions via a new neural circuit
21.08.2017 | Hokkaido University

nachricht New malaria analysis method reveals disease severity in minutes
14.08.2017 | University of British Columbia

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Nagoya physicists resolve long-standing mystery of structure-less transition

21.08.2017 | Materials Sciences

Chronic stress induces fatal organ dysfunctions via a new neural circuit

21.08.2017 | Health and Medicine

Scientists from the MSU studied new liquid-crystalline photochrom

21.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>