New 'molecular glue' helps break down antibiotic resistance enzymes in E. coli
Oxford University scientists have discovered a new approach to tackle antimicrobial resistance (AMR), using 'molecular glues' to encourage bacteria to destroy their own resistance-causing enzymes. The study has been published in Angewandte Chemie International Edition.
The new study discovered molecules that can hijack the protein-degrading machinery found in E. coli cells to destroy the bacteria's own resistance-causing enzymes. Image credit: EzumeImages, Getty Images.
For the first time, researchers in the Sir William Dunn School of Pathology and the Department of Pharmacology at Oxford University have shown that new 'molecular glues' can hijack the protein-degrading machinery found in E. coli cells, enhancing the activity of antibiotics against highly drug-resistant strains.
Since the first successful isolation and administration of penicillin by scientists in the Sir William Dunn School of Pathology during World War II, antibiotics have become some of the most used drugs to treat and prevent infections. However, due to AMR, one in six bacterial infections are now resistant to antibiotic treatments.
Developing entirely new antibiotic classes remains highly challenging, creating an urgent need for alternative approaches that can preserve the effectiveness of existing treatments. Now, 85 years after the first administration of penicillin, researchers in the same department have developed a new strategy to tackle AMR.
Dr Georgia Isom, Sir William Dunn School of Pathology and senior author of the paper said: 'Developing new antibiotics is an enormous scientific challenge and bacteria can evolve resistance to new treatments. So, we’re looking for ways to protect the antibiotics we already have.'
'Rather than following the traditional approach of developing drugs to block the function of bacterial resistance enzymes, our molecular glues can essentially chemically reprogram the bacterial cell to destroy its own resistance mechanism. This opens up a different way of tackling resistance and could help us develop new treatments that keep existing antibiotics effective for longer.'
Hijacking bacterial biology: a new way to protect β-lactam antibiotics
β-lactam antibiotics, a family of drugs that includes penicillin, are among the most widely used antibiotics in the world. One of the most common ways bacteria resist β-lactam antibiotics is by producing enzymes called β-lactamases, which destroy these drugs before they can treat infections. β-Lactamases enzymes are particularly widespread, with over 2,000 variants identified to date.
Existing approaches to combat β-lactamase enzymes aim to block their action by delivering additional drugs, known as ‘antibiotic adjuvants’, alongside the antibiotic treatment.
However, researchers recently identified a way to combat these enzymes by hijacking the protein-degrading machinery already present inside bacterial cells.
This approach, called targeted protein degradation, exploits a second type of enzyme called a protease. In bacteria, proteases are normally responsible for breaking down damaged or unwanted proteins, but by redirecting proteases towards β-lactamase enzymes researchers can potentially restore the effectiveness of existing antibiotics.
By selectively breaking down the resistance-causing enzymes, rather than simply blocking their action with inhibitors, targeted protein degradation could produce a longer-lasting effect. However, a key challenge in developing this strategy is to find the right molecules that force the bacteria to 'recruit' these proteases.
In this new work, researchers demonstrated that new ‘molecular glue’ compounds can effectively bring together the protease and β-lactamase enzymes, enhancing the breakdown of β-lactamases and protecting some of our most important antibiotics.
“Our molecular glues can essentially chemically reprogram the bacterial cell to destroy its own resistance mechanism. This opens up a different way of tackling resistance and could help us develop new treatments that keep existing antibiotics effective for longer.”
A sticky situation: identifying molecular glues
The team began by investigating a specific protease called DegP. In lab tests, researchers found that the DegP protease could break down certain types of β-lactamase enzymes, called the TEM-family of β-lactamases.
By screening a range of drugs, scientists found that one existing β-lactamase inhibitor, tazobactam, caused a small increase in the speed at which DegP broke down TEM β-lactamases. They determined that tazobactam is reacting with the active site of the β-lactamase – the key region of the enzyme where biochemical reactions occur – to cause a change in the shape of the β-lactamase, making it more susceptible for DegP to break down.
Next, the researchers investigated which other proteins DegP could degrade in E. coli, allowing them to identify specific sequences of amino acids that were more commonly found in proteins degraded by DegP.
By chemically linking these specific amino acid sequences to tazobactam, the researchers were able to produce a molecular glue called OXF-232, which greatly enhanced the speed at which DegP broke down the β-lactamase resistance enzyme in laboratory experiments.
The scientists then tested OXF-232 against a resistant E. coli strain, which produced high quantities of the β-lactamase enzyme. The molecular glues were administered in combination with the β-lactam antibiotic piperacillin. The study demonstrated that not only did OXF-232 enhance the antibiotic’s effects, but when combined with high concentrations of piperacillin it even outperformed the clinically-used drug tazobactam.
Emilia Taylor, DPhil student in the Sir William Dunn School of Pathology and the Department of Pharmacology at the University of Oxford, and lead author of the paper, said 'We were surprised to find that tazobactam, a drug used clinically in combination with β-lactam antibiotics, showed this effect in accelerating degradation by DegP. Improving our understanding of the types of proteins that DegP can break down allowed us to rationally design more effective molecular glues to degrade β-lactamase resistance enzymes.'
The team also examined the safety of these molecular glues, testing properties such as their toxicity to human cells and ability to resist being metabolised by the body. Their results showed that OXF-232 had good safety and stability properties, providing a promising platform for future drug development.
Professor Thomas Lanyon-Hogg from the Department of Pharmacology University of Oxford, and senior author of the paper, said: 'Our results show that we can design molecular glues to degrade resistance enzymes and enhance the activity of existing antibiotics, providing a much-needed new way to combat resistance. However, the really exciting question is now what other bacterial proteins or resistance mechanisms can we target for degradation using this new approach?'
The study 'Molecular Glue Degraders of TEM β-Lactamases by Periplasmic Protease DegP' has been published in Angewandte Chemie International Edition.
Read more about AMR research around the University of Oxford on the Oxford AMR Network website.
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