Healthcare (Commonwealth Union) – Antimicrobial resistance is not a distant threat—it is already here, undermining modern medicine. With no urgent action, we risk returning to a pre-antibiotic era where simple infections are deadly. Governments, healthcare professionals, farmers, and individuals all have always had a significant role to play in preserving these life-saving drugs.
To combat bacterial resistance to the tetracycline class of antibiotics, researchers at the Ineos Oxford Institute for Antimicrobial Research (IOI) have created a novel screening technique. The outcomes of this approach serve as a foundation for the creation of novel medications to treat infections that are resistant to existing medications. Chemical Science has published the results.
Among the most used antibiotics for treating urinary tract infections, respiratory tract infections, and STDs are tetracyclines. In livestock production, tetracyclines are also employed as growth boosters. However, through the production of an enzyme known as Tet(X), bacteria are developing resistance to tetracycline antibiotics. Tetracycline antibiotics are broken down by this enzyme, making them useless against bacteria.
Using a combination therapy to combat bacterial resistance mechanisms is one efficient way to restore the antibiotic’s efficacy. An inhibitor and an antibiotic are both used in a combined treatment. Before the antibiotic can treat the infection as intended, the inhibitor stops bacterial enzymes like Tet(X) from degrading it.
To bind to Tet(X), researchers at the IOI have created a fluorescent tetracycline probe. It is possible to measure the change in the fluorescent light that the probe emits when it attaches to the enzyme. Tet(X)-inhibiting molecules cause the probe to be separated from the enzyme, changing the fluorescence signal. Researchers can rapidly and accurately discover compounds that exhibit promising inhibitory activity against Tet(X) by screening large volumes of compounds by detecting variations in fluorescence.
Six intriguing Tet(X) inhibitors, including compounds already used as antipsychotics, antimalarials, and gut motility treatments, were found by the scientists using this novel technique, which examined thousands of existing medications. By using X-ray crystallography, it was discovered that the antipsychotic trifluoperazine, its chemical relative prochlorperazine, and the serotonin receptor agonist tegaserod bind inside the active site of Tet(X). In order to comprehend how the inhibitors prevent the enzyme from breaking down tetracyclines, the researchers were able to examine the three-dimensional structure of Tet(X) with the inhibitors bound thanks to crystallography. This can serve as a foundation for creating novel inhibitors.
The global increase in Tet(X)-mediated resistance poses a danger to the efficacy of last-line antibiotics, according to Professor Christopher Schofield, senior author of the study and Director of Chemistry at the Ineos Oxford Institute for Antimicrobial Research. He further indicated that to safeguard these medications, it is crucial to combine them with inhibitors that prevent the breakdown of enzymes. This tactic has proven to be quite effective with penicillin medications, such as augmentin, but it hasn’t been used with other antibiotic classes. In order to speed up the development of tetracycline inhibitors and build the foundation for next-generation combination medicines, they have discovered promising compounds and created a reliable test platform.
Dr Matthew Beech, of the Postdoctoral Research Associate, Ineos Oxford Institute for antimicrobial research and first author of the paper says “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 journal Chemical Science published a paper titled “Binding Assays Enable Discovery of Tet(X) Inhibitors that Combat Tetracycline Destructase Resistance.”
