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

More articles from Life Sciences:

nachricht The world's tiniest first responders
21.06.2018 | University of Southern California

nachricht A new toxin in Cholera bacteria discovered by scientists in Umeå
21.06.2018 | Schwedischer Forschungsrat - The Swedish Research Council

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Temperature-controlled fiber-optic light source with liquid core

In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.

Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...

Im Focus: Overdosing on Calcium

Nano crystals impact stem cell fate during bone formation

Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

Better model of water under extreme conditions could aid understanding of Earth's mantle

21.06.2018 | Earth Sciences

What are the effects of coral reef marine protected areas?

21.06.2018 | Life Sciences

The Janus head of the South Asian monsoon

21.06.2018 | Earth Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>