Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Team discovers how microbes build a powerful antibiotic

27.10.2014

Researchers report in the journal Nature that they have made a breakthrough in understanding how a powerful antibiotic agent is made in nature. Their discovery solves a decades-old mystery, and opens up new avenues of research into thousands of similar molecules, many of which are likely to be medically useful.

The team focused on a class of compounds that includes dozens with antibiotic properties. The most famous of these is nisin, a natural product in milk that can be synthesized in the lab and is added to foods as a preservative. Nisin has been used to combat food-borne pathogens since the late 1960s.


University of Illinois graduate research assistant Manuel A. Ortega, chemistry professor Wilfred van der Donk, graduate student Yue Hao, biochemistry professor Satish Nair and postdoctoral researcher Mark Walker solved a decades-old mystery into how a broad class of natural antibiotics are made.

Credit: L. Brian Stauffer

Researchers have long known the sequence of the nisin gene, and they can assemble the chain of amino acids (called a peptide) that are encoded by this gene. But the peptide undergoes several modifications in the cell after it is made, changes that give it its final form and function. Researchers have tried for more than 25 years to understand how these changes occur.

"Peptides are a little bit like spaghetti; they're too flexible to do their jobs," said University of Illinois chemistry professor Wilfred van der Donk, who led the research with biochemistry professor Satish K. Nair. "So what nature does is it starts putting knobs in, or starts making the peptide cyclical."

Special enzymes do this work. For nisin, an enzyme called a dehydratase removes water to help give the antibiotic its final, three-dimensional shape. This is the first step in converting the spaghetti-like peptide into a five-ringed structure, van der Donk said.

The rings are essential to nisin's antibiotic function: Two of them disrupt the construction of bacterial cell walls, while the other three punch holes in bacterial membranes. This dual action is especially effective, making it much more difficult for microbes to evolve resistance to the antibiotic.

Previous studies showed that the dehydratase was involved in making these modifications, but researchers have been unable to determine how it did so. This lack of insight has prevented the discovery, production and study of dozens of similar compounds that also could be useful in fighting food-borne diseases or dangerous microbial infections, van der Donk said.

Through a painstaking process of elimination, Manuel Ortega, a graduate student in van der Donk's lab, established that the amino acid glutamate was essential to nisin's transformation.

"They discovered that the dehydratase did two things," Nair said. "One is that it added glutamate (to the nisin peptide), and the second thing it did was it eliminated glutamate. But how does one enzyme have two different activities?"

To help answer this question, Yue Hao, a graduate student in Nair's lab, used X-ray crystallography to visualize how the dehydratase bound to the nisin peptide. She found that the enzyme interacted with the peptide in two ways: It grasped one part of the peptide and held it fast, while a different part of the dehydratase helped install the ring structures.

"There's a part of the nisin precursor peptide that is held steady, and there's a part that is flexible. And the flexible part is actually where the chemistry is carried out," Nair said.

Ortega also made another a surprising discovery: transfer-RNA, a molecule best known for its role in protein production, supplies the glutamate that allows the dehydratase to help shape the nisin into its final, active form.

"In this study, we solve a lot of questions that people have had about how dehydration works on a chemical level," van der Donk said. "And it turns out that in nature a fairly large number of natural products – many of them with therapeutic potential – are made in a similar fashion. This really is like turning on a light where it was dark before, and now we and other labs can do all kinds of things that we couldn't do previously."

###

Van der Donk is a Howard Hughes Medical Institute investigator. He and Nair also are faculty in the Institute for Genomic Biology at Illinois.

The National Institute of General Medical Sciences at the National Institutes of Health and the Ford Foundation supported this work.

To reach Satish Nair, call 217-333-0641; email snair@illinois.edu.

To reach Wilfred van der Donk, call 217-244-5360; email vddonk@illinois.edu.

The paper, "Structure and mechanism of the tRNA-dependent lantibiotic dehydratase NisB," is available online or to members of the media from the U. of I. News Bureau.

Diana Yates | Eurek Alert!
Further information:
http://illinois.edu/

Further reports about: Ortega amino amino acid glutamate antibiotic bacterial compounds enzyme glutamate microbes modifications

More articles from Life Sciences:

nachricht Single-stranded DNA and RNA origami go live
15.12.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard

nachricht New antbird species discovered in Peru by LSU ornithologists
15.12.2017 | Louisiana State University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: First-of-its-kind chemical oscillator offers new level of molecular control

DNA molecules that follow specific instructions could offer more precise molecular control of synthetic chemical systems, a discovery that opens the door for engineers to create molecular machines with new and complex behaviors.

Researchers have created chemical amplifiers and a chemical oscillator using a systematic method that has the potential to embed sophisticated circuit...

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Engineers program tiny robots to move, think like insects

15.12.2017 | Power and Electrical Engineering

One in 5 materials chemistry papers may be wrong, study suggests

15.12.2017 | Materials Sciences

New antbird species discovered in Peru by LSU ornithologists

15.12.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>