Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Solving mystery of how sulfa drugs kill bacteria yields 21st century drug development target

02.03.2012
More than 70 years after the first sulfa drugs helped to revolutionize medical care and save millions of lives, St. Jude Children’s Research Hospital scientists have determined at an atomic level the mechanism these medications use to kill bacteria. The discovery provides the basis for a new generation of antibiotics that would likely be harder for bacteria to resist and cause fewer side effects.

The work focused on sulfa drugs and their target enzyme, dihydropteroate synthase (DHPS). Most disease-causing microorganisms need DHPS to help make the molecule folate, which is required for the production of DNA and some amino acids. Working with enzymes from gram-negative and gram-positive bacteria, researchers used a variety of techniques to determine for the first time the key intermediate structure DHPS forms during the chemical reaction to advance folate production. The structure also explains at a molecular level how sulfa drugs function and how resistance causing mutations help bacteria withstand them.

The findings mark a major advance in both microbial biochemistry and anti-microbial drug discovery. The study is published in the March 2 issue of the journal Science.

“The structure we found was totally unexpected and really opens the door for us and others to design a new class of inhibitors targeting DHPS that will help us avoid side effects and other problems associated with sulfa drugs,” said Stephen White, Ph.D., chair of the St. Jude Department of Structural Biology and the paper’s corresponding author.

Co-author Richard Lee, Ph.D., a member of the St. Jude Department of Chemical Biology and Therapeutics, added: “Now we want to leverage this information to develop drugs against the opportunistic infections that threaten so many St. Jude patients.”

Sulfa drugs were discovered in the 1930s and became the first antibiotic in widespread use. Although the drugs were early victims of antibiotic resistance, they are still widely used against emerging infectious diseases and to prevent infections in patients with weakened immune systems, including St. Jude patients undergoing cancer chemotherapy. The growing problem of antibiotic resistance has prompted renewed interest in sulfa drugs as a possible source of new therapeutic targets, Lee said.

Previous work had shown that sulfa drugs target DHPS and work by mimicking a molecule called pABA. DHPS advances folate production by accelerating the fusion of pABA and another molecule called dihydropteridine pyrophosphate (DHPP). Until now, however, scientists did not know exactly how the DHPS reaction occurred or how sulfa drugs disrupted the process.

Working on enzymes from gram-positive Bacillus anthracis and gram-negative Yersinia pestis, the bacteria that cause anthrax and plague, researchers first used computational methods to predict the enzyme’s activity. Next they used a technique called X-ray crystallography to capture the unfolding chemical reaction and confirm the prediction. X-ray crystallography involves bombarding proteins trapped in crystals with X-rays to determine the protein structure.

Researchers showed that DHPP binds to a specific pocket in DHPS. Aided by magnesium, the binding promotes the break-up of DHPP and release of pyrophosphate. Two long flexible loops then create an intermediate structure that sets the stage for pABA to enter and bind in a second short-lived pocket, allowing pABA to fuse with the cleaved DHPP. Investigators captured all four actors in the drama in a single crystal structure, including the intermediate cleaved DHPP molecule whose existence was previously unknown.

The results showed that the mechanism involves a chemical reaction known as an Sn1 reaction rather than the anticipated Sn2 reaction. “This is a key finding for drug discovery because it reveals chemical features of the DHPS enzyme’s active site that we can exploit in developing new drugs,” said study co-author Donald Bashford, Ph.D., an associate member of the St. Jude Department of Structural Biology.

The study also provided insights into sulfa drug resistance. Investigators showed that the binding sites of pABA and the sulfa drugs overlap, but that sulfa drugs extend beyond the pocket in which pABA binds. Mutations associated with drug resistance cluster around this extended region of the pABA pocket, which explains how mutations can prevent the drugs from binding without seriously affecting the binding of pABA. The work also highlights the transitory structure made by the two DHPS loops as a target for a new class of drugs that would be difficult for bacteria to develop resistance against.

“When we set out on this project eight years ago, a goal was to truly understand the catalytic mechanism of the DHPS protein and how the inhibitors targeting it work. I am ecstatic we’ve succeeded,” Lee said. The success grew out of an interdisciplinary effort and some luck, White said. The plague enzyme turned out to be well suited to this project. Unlike the DHPS enzymes from other bacteria, the two extended loops are free to form the short-lived structure and the pABA pocket when the enzyme is immobilized in the crystal.

The study’s first authors are Mi-Kyung Yun of St. Jude and Yinan Wu, a University of Tennessee Health Sciences Center graduate student working in White’s laboratory. The other authors are Zhenmei Li, Ying Zhao, M. Brett Waddell and Antonio Ferreira, all of St. Jude.

The research was supported in part by the National Institutes of Health and ALSAC.

St. Jude Children’s Research Hospital
Since opening 50 years ago, St. Jude Children’s Research Hospital has changed the way the world treats childhood cancer and other life-threatening diseases. No family ever pays St. Jude for the care their child receives and, for every child treated here, thousands more has been saved worldwide through St. Jude discoveries. The hospital has played a pivotal role in pushing U.S. pediatric cancer survival rates from 20 to 80 percent overall, and is the first and only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. It is also a leader in the research and treatment of blood disorders and infectious diseases in children. St. Jude was founded by the late entertainer Danny Thomas, who believed that no child should die in the dawn of life. To learn more, visit www.stjude.org. Follow us on Twitter @StJudeResearch.

St. Jude Media Relations Contacts

Summer Freeman
(desk) (901) 595-3061
(cell) (901) 297-9861
summer.freeman@stjude.org

Carrie Strehlau
(desk) (901) 595-2295
(cell) (901) 297-9875
carrie.strehlau@stjude.org

Carrie Strehlau | EurekAlert!
Further information:
http://www.stjude.org

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

DGIST develops 20 times faster biosensor

24.04.2017 | Physics and Astronomy

Nanoimprinted hyperlens array: Paving the way for practical super-resolution imaging

24.04.2017 | Materials Sciences

Atomic-level motion may drive bacteria's ability to evade immune system defenses

24.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>