Scientists from the Ineos Oxford Institute for antimicrobial research (IOI) have developed a new screening method to tackle bacterial resistance to the tetracycline class of antibiotics. The results from this method provide the starting point to develop new drugs to treat drug-resistant infections. The findings have been published in Chemical Science .
Tetracyclines are among the most widely used antibiotics to treat respiratory tract infections, sexually transmitted diseases, and urinary tract infections. Tetracyclines are also used as growth promoters in livestock production. However, bacteria are becoming resistant to tetracycline antibiotics by producing an enzyme called Tet(X). This enzyme breaks down tetracycline antibiotics, rendering them ineffective against bacteria.
We have found promising compounds and developed a robust assay platform to accelerate development of tetracycline inhibitors-laying the groundwork for next-generation combination therapies.
Professor Christopher Schofield, Ineos Oxford Institute
One effective strategy to restore the activity of the antibiotic is to use a combination therapy to counter bacterial resistance mechanisms. An antibiotic combination treatment includes an antibiotic and an inhibitor. The inhibitor prevents bacterial enzymes such as Tet(X) from breaking down the antibiotic before it has its desired effect to treat the infection.
Scientists at the IOI have developed a fluorescent tetracycline probe that can bind to Tet(X). When the probe binds to the enzyme, a change in the fluorescent light emitted by the probe can be measured. Molecules that act as an inhibitor for Tet(X) cause the probe to become displaced from the enzyme, which alters the fluorescent signal. By measuring changes in fluorescence, researchers can screen high volumes of compounds to quickly and reliably identify those that show promising inhibitory activity against Tet(X).
Using this new experiment, the team screened thousands of existing drugs and identified six promising Tet(X) inhibitors, including molecules already used as antipsychotics, antimalarials, and gut motility drugs. The antipsychotic trifluoperazine, its chemical cousin prochlorperazine, and the serotonin receptor agonist tegaserod were found to bind inside Tet(X)'s active site by X-ray crystallography. The crystallography allowed the researchers to look at the three-dimensional structure of Tet(X) with the inhibitors bound to understand how they block the enzyme from destroying tetracyclines. This can provide a basis from which to design new inhibitors.
Watch a video summary of the study from the Ineos Oxford Institute
Professor Christopher Schofield
Fluorescent tetracycline probe that binds to Tet(X). Credit: Matthew Beech.
Dr Matthew Beech , Postdoctoral Research Associate, Ineos Oxford Institute for antimicrobial research and first author of the paper said: 'Our newly-developed fluorescent probe has helped us discover existing medicines such as antipsychotics and antimalarials that can be used to protect tetracycline antibiotics. Crystal structures have also revealed how these compounds latch onto Tet(X), unlocking new design strategies. We will now work to refine these molecules, with the ultimate aim of delivering a new combination therapy that can be used in clinical settings.'
The study 'Binding Assays Enable Discovery of Tet(X) Inhibitors that Combat Tetracycline Destructase Resistance' has been published in the journal Chemical Science .
