Key discoveries offer significant hope of reversing antibiotic resistance

Two recent studies
led by the University of Bristol provide significant new hope in the fight
against antibiotic resistance. By identifying what makes some bacteria
resistant to the most commonly prescribed antibiotics, and how this can be
reversed, the findings have demonstrated potentially life-saving consequences
and could help reverse the tide of antibiotic resistance.

Resistance to
antibiotics is becoming increasingly prevalent and threatens to undermine
healthcare systems across the globe. Antibiotics including penicillins,
cephalosporins and carbapenems are known as β-lactams and are the most commonly
prescribed worldwide.

In the first paper,
University of 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; in the other, bacteria produce
an enzyme (a β-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
β-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 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.

They found both
inhibitors failed to consistently protect the β-lactam antibiotic, ceftazidime,
from attack by the β-lactamase enzyme. However, when paired with a different
β-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 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. 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 β-lactamase inhibitors. At the risk of
sounding like King Canute, 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.”