Scientists at the Ineos Oxford Institute (IOI) have developed a new screening method to address the growing issue of antimicrobial resistance in bacteria. Tetracyclines, widely used antibiotics for various infections, are becoming less effective due to bacterial resistance mechanisms involving an enzyme called Tet(X), which breaks down these antibiotics.
To combat this, researchers have created a fluorescent tetracycline probe that binds to Tet(X). The probe emits a measurable change in fluorescent light when bound to the enzyme. When inhibitors displace the probe from Tet(X), it alters the fluorescence signal, allowing scientists to identify compounds with inhibitory activity against Tet(X).
Professor Christopher Schofield from IOI stated: "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."
The team screened thousands of drugs using this method and identified six potential Tet(X) inhibitors, including existing antipsychotics, antimalarials, and gut motility drugs. X-ray crystallography showed how molecules like trifluoperazine and tegaserod bind inside Tet(X)’s active site.
Dr. Matthew Beech highlighted the significance of their findings: "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."
This research is published in Chemical Science under the title ‘Binding Assays Enable Discovery of Tet(X) Inhibitors that Combat Tetracycline Destructase Resistance’.