Improving our antibiotics


In general, the antibiotics that are prescribed by your GP work. Complete the prescribed course and your symptoms have gone. But in some cases, the bacteria causing the illness have developed a resistance to the drugs. We need to find a way to improve these drugs so that they can overcome this resistance. But we need to know how our drugs work before we can improve them, and one way to do this is by producing a 3D molecular image of the drug/inhibitor in action. Knowing 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.

A collaboration of scientists have used Diamond Light Source to solve the 3D structure of the penicillin binding protein PBP3 from Pseudomona aeruginosa (P. aeruginosa), a common bacterium which can cause disease in animals and humans. The organism is particularly dangerous to those with a compromised immune system, often causing secondary infections that can be fatal to the patient. And to make matters worse, it can easily thrive on most surfaces, including medical equipment, which can result in cross-infections in hospitals and clinics.

The research team from the Wellcome Trust Centre for Human Genetics (WTCHG) and the University of Dundee's College of Life Sciences, are targeting P. aeruginosa because of its clinical prevalence and its ability to cause secondary ailments, and have selected PBP3 because it is a proven therapeutic target. The team used Diamond's protein crystallography facilities to solve three structures: the protein in native form; and the protein linked to two important antibiotics, carbenicillin and ceftazidime.

Dr Ray Owens of the Oxford Protein Production Facility, WTCHG, says: "The aim of the project is to understand the interaction between the antibiotic and its target at the molecular level, with a view to develop the next generation of antibiotics and combat the problem of drug resistance."

Their structures 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.

Jan 11 PBP3Overall structure of PBP3 with bound carbenicillin


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 diseases respiratory and skin infections, gastro-intestinal and sexually transmitted diseases.

For more information on Dr Owen's research, click here.


Crystal Structures of Penicillin-Binding Protein 3 from Pseudomonas aeruginosa: Comparison of Native and Antibiotic-Bound Forms
Sainsbury S, Bird L, Rao V, Shepherd SM, Stuart DI, Hunter WN, Owens RJ, Ren J.
Journal of Molecular Biology, Volume 405, Issue 1, 7 January 2011, Pages 173-184.