Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Small molecule acts as on-off switch for nature's antibiotic factory

29.08.2014

Tells Streptomyces to either veg out or get busy

Scientists have identified the developmental on-off switch for Streptomyces, a group of soil microbes that produce more than two-thirds of the world's naturally derived antibiotic medicines.


The soil bacteria Streptomyces form filamentous branches that extend into the air to create spiraling towers of spores. Duke researchers have discovered the switch that can turn off sporulation and turn on antibiotic production.

Credit: US Centers for Disease Control and Prevention


Duke structural biologists have found a unique interaction between a small molecule called cyclic-di-GMP and a larger protein called BldD that ultimately controls whether a bacterium spends its time in a vegetative state or making antibiotics.

Credit: Maria Schumacher, Duke University

Their hope now would be to see whether it is possible to manipulate this switch to make nature's antibiotic factory more efficient.

The study, appearing August 28 in Cell, found that a unique interaction between a small molecule called cyclic-di-GMP and a larger protein called BldD ultimately controls whether a bacterium spends its time in a vegetative state or gets busy making antibiotics.

Researchers found that the small molecule assembles into a sort of molecular glue, connecting two copies of BldD as a cohesive unit that can regulate development in the Gram-positive bacteria Streptomyces.

"For decades, scientists have been wondering what flips the developmental switch in Streptomyces to turn off normal growth and to begin the unusual process of multicellular differentiation in which it generates antibiotics," said Maria A. Schumacher, Ph.D., an associate professor of biochemistry at the Duke University School of Medicine. "Now we not only know that cyclic-di-GMP is responsible, but we also know exactly how it interacts with the protein BldD to activate its function."

Streptomyces has a complex life cycle with two distinct phases: the dividing, vegetative phase and a distinct phase in which the bacteria form a network of thread-like filaments to chew up organic debris and churn out antibiotics and other metabolites. At the end of this second phase, the bacteria form filamentous branches that extend into the air to create spiraling towers of spores.

In 1998 researchers discovered a gene that kept cultured Streptomyces bacteria from creating these spiraling towers of fuzz on their surface. They found that this gene, which they named BldD to reflect this "bald" appearance, also affected the production of antibiotics.

Subsequent studies have shown that BldD is a special protein called a transcription factor, a type of master regulator that binds DNA and turns on or off more than a hundred genes to control biological processes like sporulation. But in more than a decade of investigation, no one had been able to identify the brains behind the operation, the molecule that ultimately controls this master regulator in Streptomyces.

Then scientists at the John Innes Centre in the United Kingdom -- where much of the research on Streptomyces began -- discovered that the small molecule cyclic-di-GMP is generated by several transcription factors regulated by BldD. The researchers did a quick test to see if this small molecule would itself bind BldD, and were amazed to find that it did. They contacted longtime collaborators Schumacher and Richard G. Brennan Ph.D. at Duke to see if they could take a closer look at this important interaction.

The Duke team used a tool known as x-ray crystallography to create an atomic-level three-dimensional structure of the BldD-(cyclic-di-GMP) complex.

BldD normally exists as a single molecule or monomer, but when it is time to bind DNA and suppress sporulation, it teams up with another copy of itself to do the job. The 3D structure built by the researchers revealed that these two copies of BldD never physically touch, and instead are stuck together by four copies of cyclic-di-GMP.

"We have looked through the protein databank and scoured our memories, but this finding appears to be unique," said Brennan, who is a professor and chair of biochemistry at Duke University School of Medicine. "We have never seen a type of structure before where two monomers become a functional dimer, with no direct interaction between them except a kind of small-molecule glue."

To confirm their findings, Schumacher determined several crystal structures from different flavors of bacteria (S. venezuelae and S. coelicolor) and came up with the same unusual result every time.

Now that the researchers know how cyclic-di-GMP and BldD can become glued together to turn off sporulation and turn on antibiotic production, they would like to know how the complex can become unglued again to flip the switch the other way.

The research was supported by a Long Term EMBO Fellowship (ALTF 693-2012), a Leopoldina Postdoctoral Fellowship, the Biotechnology and Biological Sciences Research Council (BB/H006125/1), the MET Institute Strategic Programme, and the Duke University School of Medicine.

###

CITATION: "Tetrameric c-di-GMP mediates effective transcription factor dimerization to control Streptomyces development," Natalia Tschowri, Maria A. Schumacher, Susan Schlimpert, Nagababu Chinnam, Kim C. Findlay, Richard G. Brennan, and Mark J. Buttner. Cell, August 28, 2014.

Karl Bates | Eurek Alert!

Further reports about: DNA Medicine Streptomyces antibiotics bacteria controls discovered factor glue structure transcription

More articles from Life Sciences:

nachricht Navigational view of the brain thanks to powerful X-rays
18.10.2017 | Georgia Institute of Technology

nachricht Separating methane and CO2 will become more efficient
18.10.2017 | KU Leuven

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Osaka university researchers make the slipperiest surfaces adhesive

18.10.2017 | Materials Sciences

Space radiation won't stop NASA's human exploration

18.10.2017 | Physics and Astronomy

Los Alamos researchers and supercomputers help interpret the latest LIGO findings

18.10.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>