24 Oct 2017
Resistance to antibiotics is one of the most pressing issues in global healthcare, with β-lactams such as penicillins, cephalosporins and carbapenems being the most commonly prescribed.
Building on earlier research into β-lactam antibiotic resistance, chemists at the Universities of Bristol, Oxford and Leeds have demonstrated an effective pairing of antibiotics and enzyme inhibitors, which killed even the most resistant bacteria.
Image: Iqbal Osman/Flickr
In the earlier study, the Bristol researchers defined the relative importance of two mechanisms associated with β-lactam antibiotic resistance. In one, bacteria restrict the entry of antibiotics into the cell; but more significantly, in the other, bacteria produce an enzyme (a β-lactamase), which destroys any antibiotic that gets into the cell – implying that if chemicals could be developed to inhibit β-lactamase enzymes, a significant proportion of antibiotic resistance could be reversed.
The joint authors of the second study looked into the effectiveness of two types of β-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.
While both inhibitors failed to consistently protect the β-lactam antibiotic ceftazidime from attack by the β-lactamase enzyme, when paired with the β-lactam antibiotic aztreonam, the inhibitors worked extremely well. They were able to kill even the highly resistant bacterium Stenotrophomonas maltophilia, which causes severe infections in immunocompromised patients and is usually resistant to all β-lactam antibiotics because it produces two β-lactamase enzymes.
Entering clinical use
Dr Matthew Avison, Reader in Molecular Bacteriology at the University of Bristol's School of Cellular and Molecular Medicine, and senior author for both studies said, 'Our bacteriology research has further demonstrated that β-lactamases are the real "Achilles heel" of antibiotic resistance in bacteria that kill thousands of people in the UK every year.
‘Structural/mechanistic work on β-lactamase enzymes, including that led by my colleague Dr Jim Spencer, is helping to drive the discovery of wave after wave of β-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 β-lactamase inhibitors have recently been licenced for clinical use: avibactam and vaborbactam. Dr Avison claims the team’s research ‘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.’
The World Health Organisation recently placed cephalosporin and carbapenem-resistant Gram-negative bacteria of the Enterobacteriaceae and Non-Fermenter groups at the top of its Priority List of Pathogens where R&D of novel treatment strategies is needed.
‘At the risk of sounding like King Canute’, Dr Avison said, ‘it is the first time for a decade that there is some genuine positivity about our ability to turn back the rising tide of β-lactam antibiotic resistance.’
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