Oxford scientists have developed a new screening method which reveals new ways of combating antimicrobial resistant bacteria.
In research published by Chemical Science, scientists at the Ineos Oxford Institute for Antimicrobial Research (IOI) have identified several compounds that could make tetracyclines (a type of antibiotic) effective against drug-resistant bacteria.
Tetracyclines are mostly used in treating respiratory tract infections, urinary tract infections, and sexually transmitted diseases. However, increasing bacterial resistance is making them less and less useful. An enzyme called Tet(X), which breaks down tetracycline antibiotics and, essentially, makes them ineffective, is especially resistant.
The IOI team has developed a “fluorescent tetracycline probe” which binds to Tet(X). This means they can identify any substances which block Tet(X). As a result, scientists can test thousands of existing drugs to test if they have the potential to block resistance to antibiotics.
Three of the six drugs were already in clinical use. X-ray crystallography showed that these compounds bind within Tet(X)’s active site, providing insight into how they block the enzyme and suggesting routes for future drug design.
Professor Christopher Schofield, Director of Chemistry at IOI, said: “The global rise of Tet(X)-mediated resistance threatens to undermine the effectiveness of last-line antibiotics. Pairing these antibiotics with inhibitors that block enzyme degradation is essential to protect these drugs.
“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.”
Dr Matthew Beech, Postdoctoral Research Associate at IOI and first author of the paper, also 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 is titled “Binding Assays Enable Discovery of Tet(X) Inhibitors that Combat Tetracycline Destructase Resistance”.
