Key Strides Being Made in The Battle Against Antibiotics Resistance

By Jane Farrell

Resistance to antibiotics is becoming increasingly prevalent and threatens to undermine healthcare systems across the globe.

Now, though, scientists appear to have discovered a way to combat it.

Researchers from the University of Bristol, in the UK, defined the relative importance of two mechanisms associated with resistance to beta-lactam antibiotics. (Antibiotics including penicillins, cephalosporins and carbapenems are known as beta-lactams and are the most commonly prescribed antibiotics worldwide.)

In one mechamism, bacteria restrict the entry of antibiotics into the cell; in the other, bacteria produce an enzyme (a beta-lactamase), which destroys any antibiotic that gets into the cell. The latter was found to be the more important of the two mechanisms. These findings imply that if chemicals could be developed to inhibit beta-lactamase enzymes, a significant proportion of antibiotic resistance could successfully be reversed.

Building on these findings, and working in partnership with chemists at the University of Oxford and the University of Leeds, Bristol researchers also studied the effectiveness of two types of beta-lactamase enzyme inhibitor in a bacterium known to be highly resistant to common antibiotics.

Using a variety of approaches, the authors studied avibactam, an inhibitor that has recently been introduced into clinical practice, and a “bicyclic boronate” inhibitor, which was first reported by the Oxford/Leeds/Bristol team in 2016.

They found both inhibitors failed to consistently protect the beta-lactam antibiotic, ceftazidime, from attack by the beta-lactamase enzyme. However, when paired with a different beta-lactam antibiotic, aztreonam, the inhibitors worked extremely well and killed some of the most resistant bacteria ever seen in the clinic.

Dr Matthew Avison, Reader in Molecular Bacteriology from the University of Bristol’s School of Cellular and Molecular Medicine, and senior author for both studies, said: “Structural/mechanistic work on beta-lactamase enzymes…is helping to drive the discovery of wave after wave of beta-lactamase inhibitors, including the potentially game-changing bicyclic boronate class, shown to be effective in our research, and recently successful in phase one clinical trials.

“Two beta-lactamase inhibitors have recently been licensed for clinical use: avibactam and vaborbactam. Our work shows that avibactam might more successfully be deployed with aztreonam instead of ceftazidime as its antibiotic partner. We are delighted to see that this combination has entered clinical trials, and has recently saved the life of a patient in the USA who was suffering from a previously untreatable infection.

“This is an exciting time for researchers studying beta-lactamase inhibitors. It is the first time for a decade that there is some genuine positivity about our ability to turn back the rising tide of beta-lactam antibiotic resistance.”