Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Team develops new weapon to fight disease-causing bacteria, malaria

16.02.2010
Researchers report that they have discovered – and now know how to exploit – an unusual chemical reaction mechanism that allows malaria parasites and many disease-causing bacteria to survive. The research team, from the University of Illinois, also has developed the first potent inhibitor of this chemical reaction.

The findings appear in the Proceedings of the National Academy of Sciences.

"There is an urgent need for new drugs to combat malaria and bacterial diseases such as tuberculosis that are becoming resistant to existing treatments," said chemistry professor Eric Oldfield, who led the study. "Millions of people have tuberculosis, for example, and some of the bacterial strains that cause TB are completely drug resistant," he said. The parasites that cause malaria also have become resistant to quinine, chloroquine and now, artemisinin, three common treatments for the disease.

The new study focuses on an essential chemical pathway that occurs in malaria parasites and in most bacteria but not in humans or other animals, making it an ideal drug target. Several teams of researchers have spent nearly a decade trying to understand an important player in this cascade of chemical reactions, an enzyme known as IspH. This enzyme promotes the synthesis of a class of compounds, called isoprenoids, which are essential to life.

"Isoprenoids are the largest class of compounds on the planet," Oldfield said. "There are over 60,000 of them. Cholesterol is an isoprenoid. The orange beta-carotene in carrots is an isoprenoid. And bacterial cell walls are made using isoprenoids."

IspH (rhymes with "lisp, H") is a reductase. It acts on a cellular compound, HMBPP, "reducing" it by adding two electrons and two protons to it in an early stage of isoprenoid biosynthesis. Understanding the structure and function of IspH, researchers hope, will allow them to find a way to block it and shut down production of isoprenoids in the disease-causing bugs.

Oldfield and his colleagues already had discovered the structure of IspH, which has a cube-like cluster of iron and sulfur atoms at its core. They determined that the core contained four iron and four sulfur atoms, a finding they published in the Journal of the American Chemical Society in 2008. (Other researchers later maintained that there were only three iron atoms in IspH, but recently amended their proposed structure to include four iron atoms.)

In the search for possible compounds that would inhibit IspH, Oldfield and his colleagues, including graduate student Weixue Wang, turned to a powerful technique, called electron paramagnetic resonance (EPR), which allows researchers to determine molecular structure.

"We thought we could use this EPR technique to see how inhibitors bind to IspH," Oldfield said. "But some of the early EPR spectra that Weixue got were really unusual."

To make sense of what he was seeing, Wang reviewed other studies and discovered that the unusual spectra closely resembled those seen with another enzyme, nitrogenase, which also has a metal-sulfur core and also acts as a reductase. His EPR spectra, along with data obtained using computational methods, convinced the researchers that during the chemical reaction, IspH and the compound that it reduces, HMBPP, form an intermediate that involves a highly unusual iron-carbon bond.

"People have been studying iron-sulfur clusters for 40 or 50 years," Wang said. "But they never discovered such interactions between iron and carbon in four-iron, four-sulphur proteins."

The researchers noted that a chemical compound, acetylene, blocks the activity of nitrogenase. They reasoned that this compound – or a similar one – might also inhibit IspH.

They made derivatives of acetylene and engineered a compound, which they call PPP, to test against IspH. Laboratory tests revealed that PPP is in fact a powerful inhibitor of IspH.

"It's one thousand times more potent than previous inhibitors," Oldfield said.

PPP has not yet been tested in cells, and much work remains to be done to develop anti-malarial or antibacterial drugs based on the new findings, Oldfield said.

"We're really at the initial, key stage, which is understanding structure and function and getting clues for inhibitors – drug leads," he said. "But there are a finite number of proteins unique to bacteria and malaria parasites that can be targeted for the development of new drugs. And everyone agrees that this enzyme, IspH, is a tremendous target."

"The Oldfield group has uncovered completely unexpected behavior for iron-sulfur clusters," said U. of I. chemistry professor Thomas B. Rauchfuss, who was not involved in the study. "We can expect that their discovery will lead to intense follow-up studies because the results have obvious implications for both biomedicine and organometallic catalysis. Iron-sulfur clusters are found in all forms of life, so when a new function is discovered, it is big news to a wide community."

The National Institute of General Medical Sciences at the National Institutes of Health funded this research.

Editor's note: To reach Eric Oldfield, call 217- 333-3374; e-mail eo@chad.scs.uiuc.edu.

The paper, "Bioorganometallic mechanism of action, and inhibition, of IspH," is available from the University of Illinois News Bureau. See contact information, above.

Diana Yates | EurekAlert!
Further information:
http://www.illinois.edu

More articles from Life Sciences:

nachricht Researchers develop eco-friendly, 4-in-1 catalyst
25.04.2017 | Brown University

nachricht Transfecting cells gently – the LZH presents a GNOME prototype at the Labvolution 2017
25.04.2017 | Laser Zentrum Hannover 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: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

NASA's Fermi catches gamma-ray flashes from tropical storms

25.04.2017 | Physics and Astronomy

Researchers invent process to make sustainable rubber, plastics

25.04.2017 | Materials Sciences

Transfecting cells gently – the LZH presents a GNOME prototype at the Labvolution 2017

25.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>