The Role of Beta-Lactamase in Antibiotic Resistance
- Bacteria restricts the entry of antibiotics into the cell.
- Bacteria also produce an enzyme (a beta-lactamase), which destroys any antibiotic that gets into the cell.
- With chemicals to inhibit beta-lactamase enzymes, antibiotic resistance could be reversed.
In the first paper, University of Bristol researchers defined the relative importance of two mechanisms associated with beta-lactam antibiotic resistance. In one, 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.
Chemicals to Combat Antibiotic Resistance
These findings imply that if chemicals could be developed to inhibit beta-lactamase enzymes, a significant proportion of antibiotic resistance could successfully be reversed.
‘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, in the second paper, Bristol researchers 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 & Molecular Medicine, and senior author for both studies said: "Our bacteriology research has further demonstrated that beta-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 beta-lactamase enzymes, including that led by my colleague Dr Jim Spencer, 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 be more successfully 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."
- Keiichi Hiramatsu,Masayuki Igarash et al. Curing Bacteria of Antibiotic Resistance: Reverse Antibiotics, a Novel Class of Antibiotics In Nature, International Journal of Antimicrobial Agents http://dx.doi.org/10.1016/j.ijantimicag.2012.02.007