Antibiotic Resistance: Helping the Battle Against Disease

Researchers at the University of Leeds have been harnessing one of the biggest problems facing health services—antibiotic resistance—to develop drugs to combat some of the most intractable diseases.

Lead scientist, Professor Sheena Radford, FRS Director of the Astbury Centre for Structural Molecular Biology, said: “Until now, we haven’t had effective ways to identify drugs to combat amyloid formation. Amyloid-prone proteins often don’t have a clearly defined structure, which makes it very difficult to identify areas to target with drugs. Also, because amyloid-causing proteins have a tendency to stick together, they can be very hard to study in the lab. This study shows a way of getting around these problems by grafting amyloid-prone sequences into enzymes which break down antibiotics.”

First, amyloid-prone sequences from target proteins are attached to antibiotic degrading beta-lactamase enzymes. Bacteria carrying the modified enzymes are combined in laboratory dishes with the antibiotic. Normally, the presence of the beta-lactamase would disable the antibiotic, allowing bacterial growth.

However, the amyloid-causing sequences act as “Trojan horses” in the beta-lactamase, preventing it from attacking the antibiotic and therefore stopping the tell-tale bacterial growth. Next, the researchers add chemicals and test whether they disable the amyloid-causing sequences, freeing the beta-lactamase to attack the antibiotic and allowing bacterial growth

The study identified one chemical—L-dopamine—that blocks amyloid deposits forming from sequences associated with type II diabetes. However, the real significance of the work is its potential for generic use with any protein associated with amyloid disease.

Co-author Dr David Brockwell, Associate Professor in the University’s School of Molecular and Cellular Biology, said: “If you can insert a protein sequence into beta-lactamase, you are likely to be able to use this technique as a screen for chemicals capable of inhibiting its aggregation. You can screen thousands of compounds by putting them through this test.”

Professor Radford said: “It is important to stress that an efficient screen is only one step in the journey toward drug discovery. The power of our study is that it provides the first step on this path by showing us the type of molecules we should be looking at to inhibit a particular disease-causing protein.”

Another application of the new technique could be for use in the manufacture of bio-pharmaceuticals, a class of protein-based drugs that includes many of the highest grossing modern drugs.