Navigation Links
Solving mystery of how sulfa drugs kill bacteria yields 21st century drug development target
Date:3/1/2012

MEMPHIS, Tenn. -- 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.


'/>"/>
Contact: Carrie Strehlau
media@stjude.org
901-595-2295
St. Jude Children's Research Hospital
Source:Eurekalert

Related medicine news :

1. Experts Optimistic About Solving Puzzle of Alzheimers
2. Work Teams Who Share Negative Emotions Better at Problem-Solving
3. IOM and NAE launch collegiate challenge aimed at solving health problems
4. ISU research raises hope for solving Parkinsons disease puzzle
5. Solving a traditional Chinese medicine mystery
6. Presumed consent not answer to solving organ shortage in US, researchers say
7. Contact Dermatitis Can Be Irritating, Especially When the Cause is a Mystery
8. Scientist, Dr Staninger, Unlocks the Mystery of Morgellons Disease
9. U of T researchers crack splicing code, solve a mystery underlying biological complexity
10. Parkinsons Transplant Mystery Solved, Researchers Say
11. Is Frequency the Future of Medicine or an Ancient Mystery Revealed?
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:6/26/2016)... (PRWEB) , ... June 27, 2016 , ... Quality metrics ... yet in many ways they remain in the eye of the beholder, according to ... a publication of The American Journal of Managed Care. For the full issue, ...
(Date:6/26/2016)... ... June 26, 2016 , ... Pixel Film Studios Released ProSlice Levels, a Media ... give their videos a whole new perspective by using the title layers in ... Studios. , ProSlice Levels contains over 30 Different presets to choose from. ...
(Date:6/26/2016)... ... June 26, 2016 , ... Brent Kasmer, a legally blind and certified personal trainer is ... a fitness app. The fitness app plans to fix the two major problems leading the ... one size fits all type program , They don’t eliminate all the reasons ...
(Date:6/25/2016)... ... 25, 2016 , ... Experts from the American Institutes for ... Meeting June 26-28, 2016, at the Hynes Convention Center in Boston. , AIR ... care planning, healthcare costs and patient and family engagement. , AIR researchers will ...
(Date:6/25/2016)... ... , ... The temporary closing of Bruton Memorial Library on June 21 due to a possible ... often overlooked aspect of head lice: the parasite’s ability to live away from a human ... but a necessary one in the event that lice have simply gotten out of control. ...
Breaking Medicine News(10 mins):
(Date:6/24/2016)... 24, 2016  Collagen Matrix, Inc., ("Collagen Matrix") ... manufacturing of collagen and mineral based medical devices ... Bill Messer has joined the company ... leverage the growing portfolio of oral surgery, neurosurgery, ... Bill joins the Collagen Matrix executive team as ...
(Date:6/24/2016)... 24, 2016 Research and ... "Structural Electronics 2015-2025: Applications, Technologies, Forecasts" report ... In-Mold Electronics, Smart Skin, Structural Health Monitoring, ... Structural electronics involves electronic and/or electrical components ... replacing dumb structures such as vehicle bodies or ...
(Date:6/24/2016)... Research and Markets has announced the addition of the ... to their offering. ... World Market for Companion Diagnostics covers the world market for ... report includes the following: , World IVD ... (N. America, EU, ROW), 2015-2020 , World IVD Companion ...
Breaking Medicine Technology: