Corporate Banner
Satellite Banner
Biomolecular Screening
Scientific Community
 
Become a Member | Sign in
Home>News>This Article
  News
Return

Visualising the Problem may help to Improve Antibiotics

Published: Monday, January 17, 2011
Last Updated: Monday, January 17, 2011
Bookmark and Share
Researchers from the Universities of Dundee and Oxford have made a significant breakthrough in understanding how resistance to antibiotics might be overcome, by producing the first ever 3D molecular image of a key drug target and showing how drugs bind to it.

Professor William Hunter, from the College of Life Sciences at Dundee, coordinates the EU-funded Aeropath project, which is designed to advance early stage drug discovery against Pseudomonas aeruginosa (P. aeruginosa), a common bacterium that can cause serious diseases in animals and humans.

This bacterium is particularly troublesome since it has developed resistance to many common antibiotics and is an important pathogen of burns victims, immuno-compromised patients for example due to chemotherapy or other conditions, and also to cystic fibrosis patients.

In collaboration with colleagues from Oxford’s Division of Structural Biology, and the Oxford Protein Production Facility (OPPF) using state of the art facilities at the Diamond Light Source synchrotron in Oxfordshire, the team were able to determine the accurate chemical structure of the penicillin binding protein PBP3 from Pseudomonas aeruginosa.

The research was made possible by using a machine called a synchrotron. It houses a large ring-shaped vacuum tube similar in size to Hampden Park, in which electrons are accelerated at close to the speed of light and manipulated by special magnets to give off very intense X-rays. These X-rays were then used to probe tiny PBP3 crystals through diffraction methods, enabling the researchers to determine the 3D structure of the protein.

BHIMAGE_2.JPGKnowing the 3D structure of an antibiotic bound to its target protein elucidates the molecular mechanism – revealing how the drug works and how it could be modified, for example, to overcome resistance. The structures identified suggest that there could be scope to develop new drugs that work in combination with existing PBP inhibitors to make them more effective and able to overcome resistance. 

The research has been published in the most recent edition of the Journal of Molecular Biology. Now that the Dundee/Oxford team have established the exact chemical structure of the protein, researchers at these and other institutions will be able to try and develop new inhibitors and therapies.

Using the Diamond synchrotron the team were able to efficiently determine the 3D structure of the penicillin binding protein PBP3, and this may have significant impact in the future development of antibiotics, according to Professor Hunter.

“Having this accurate 3D picture of the enzyme and knowing where these molecules called inhibitors bind is critical,” he said. “It gives us a clear understanding of the molecular interactions that are involved in inhibiting this drug target. If we didn’t have that information we would be looking to characterise interactions by other less accurate methods.

“In those circumstances, you’re essentially working blind. You have to do many more experiments to get the understanding we have been able to get by doing this crystal structure.

“The objective of our work is to help advance understanding of potentially new targets for the development of therapies against Gram negative infections, which are a real problem because of the increase in drug resistance and in some cases, these are just tough beasts to kill.

“Pseudomonas aeruginosa is something we’re particularly interested in as this causes a lot of problems for people whose immune system is compromised either due to transplant surgery, chemotherapy, people who have HIV/AIDS, people who are recovering from burns and also young people with cystic fibrosis whose lungs struggle to cope with dangerous Gram negative bacteria.

“Because these organisms are so tough, we need new ideas for drugs and the way to do that is to find new targets or exploit old targets and come out with new compounds that will hit the old targets.

“We interact with a number of colleagues to look at these targets. In order to make sure we were casting our net as wide as possible I set up a collaboration with this group in Oxford to get them to take on additional targets and, using the excellent facilities at the Diamond synchrotron, they were fantastic and did a very good job of getting the structure of the penicillin binding protein PBP3.

“For many years, this has been a key therapeutic target but the organisms can change, mutate, and develop drug resistance.

“Now that we’ve got this 3D picture, we know where all the atoms are, we know how this molecule works, and the challenge is to use this information to come up with new small molecules that will stop PBP3 from working. This is a medical problem that deserves a solution and we are looking at several possible pathways of modifying existing drugs to supplement the arsenal of antibiotics.”

The team used Diamond Light Source’s protein crystallography facilities to solve three structures: the protein in native form; and the protein linked to two important antibiotics, carbenicillin and ceftazidime.

A common feature observed in the crystal structures of PBPs is the flexibility of the active sites. This property plays a key role in the bacteria’s ability to develop a resistance to drugs; the resistance mechanism works by mutating the protein. For binding of the drug to occur, the protein bends towards the inhibitor. The conformational change introduced by the inhibitor opens up a small pocket within the active site.

From their 3D structures of the mechanism, the group are able to characterise these pockets with a view to targeting them with a new type of inhibitor that restricts the active site “breathing” i.e. restrict the flexibility of the protein. This new inhibitor could be used in conjunction with existing antibiotics to combat drug resistance.

Overall, the group’s findings will allow discussions of different approaches to inhibit PBPs and potentially lead to new ways of combating P. aeruginosa and related bacteria which cause respiratory diseases and skin infections, gastro-intestinal and sexually transmitted diseases.

The Dundee team is funded by the European Commission, while the Medical Research Council (MRC) provide funding for the Oxford researchers’ work.


Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,900+ scientific posters on ePosters
  • More than 4,200+ scientific videos on LabTube
  • 35 community eNewsletters


Sign In



Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into TechnologyNetworks.com you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Dundee Researchers Seek to Beat "Molecular Obesity"
Researchers from the University of Dundee have come up with a new innovative approach in the quest to reduce failure rates in the drug discovery process.
Thursday, January 26, 2012
University of Dundee First to Install Biacore 4000 SPR System
The system will be used to focus on developing biophysical fragment based screening methodologies for efficient drug discovery.
Wednesday, June 16, 2010
New Programme Leader Appointed to Dundee MRC Unit
MRC Protein Phosphorylation Unit recruits Dr Ian Ganley from the Memorial Sloan Kettering Cancer Center.
Tuesday, March 02, 2010
Dundee Centre to Focus on Cancer Prevention and Screening
Cancer experts from across a wide range of disciplines at the University of Dundee are to pool their efforts to push forward research into developing effective programmes of prevention and early screening for the disease.
Monday, October 26, 2009
Scientific News
Charting Kidney Cancer Metabolism
Changes in cell metabolism are increasingly recognized as an important way tumors develop and progress, yet these changes are hard to measure and interpret. A new tool designed by MSK scientists allows users to identify metabolic changes in kidney cancer tumors that may one day be targets for therapy.
Insights into the Function of the Main Class of Drug Targets
About thirty percent of all medical drugs such as beta-blockers or antidepressants interact with certain types of cell surface proteins called G protein coupled receptors.
Visualizing a Cancer Drug Target at Atomic Resolution
Using cryo-electron microscopy, researchers were able to view, in atomic detail, the binding of a potential small molecule drug to a key protein in cancer cells.
Honey’s Potential to Save Lives
The healing powers of honey have been known for thousands of years.
3-D Printed Lifelike Liver Tissue for Drug Screening
A team led by engineers at the University of California, San Diego has 3D-printed a tissue that closely mimics the human liver's sophisticated structure and function. The new model could be used for patient-specific drug screening and disease modeling.
Cytoskeleton Crew
Findings confirm sugar's role in helping cancers survive by changing cellular architecture.
Biomarker for Recurring HPV-Linked Oropharyngeal Cancers
A look-back analysis of HPV infection antibodies in patients treated for oropharyngeal (mouth and throat) cancers linked to HPV infection suggests at least one of the antibodies could be useful in identifying those at risk for a recurrence of the cancer, say scientists at the Johns Hopkins University.
Valvena, GSK Sign New R&D Collaboration
Valneva to supply process development services for EB66® -based Influenza vaccines.
Light Signals from Living Cells
Fluorescent protein markers delivered under high pressure.
Cellular 'Relief Valve'
A team led by scientists at The Scripps Research Institute (TSRI) has solved a long-standing mystery in cell biology by showing essentially how a key “relief-valve” in cells does its job.
SELECTBIO

Skyscraper Banner
Go to LabTube
Go to eposters
 
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,900+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,200+ scientific videos
Close
Premium CrownJOIN TECHNOLOGY NETWORKS PREMIUM FOR FREE!