Combating antibiotic resistance

Metallo-beta-lactamases (MBLs) are enzymes produced by drug-resistant bacteria and play a major role in antibiotic resistance.  Bacteria are even using MBLs to develop resistance to the latest generation of antibiotics, such as the carbapenems, which are often considered the drug of last resort.  By catalysing the hydrolysis of the β-lactam ring, which is present in all penicillin-related antibiotics, MBLs destroy the molecule’s antibacterial properties.

Scientists at the University of Oxford have developed a method to overcome this potentially devastating problem and extend the lifetime of currently used β-lactam-based antibiotics.

A global issue

Antibiotic resistance is considered to be the most important global public health issue as an increasing number of therapies have become less effective in treating various bacterial infections.  The World Health Organisation calculates that this growing threat costs the US health system alone $21 billion to $34 billion per year.  Another report from the Chief Medical Officer for England compares the threat to that of climate change, whilst the European Centre for Disease Control estimates that multidrug-resistant infections cost the EU over €1.5 billion per year and cause 25,000 deaths.  There is a strong social and commercial need to tackle the issue but there are very few new antibiotic treatments available.

 

A pressing clinical need

Beta-lactams are the most widely used class of antibiotics and are therefore among the most important medicines currently in use.  The use of beta-lactams is presently compromised by resistance mechanisms, most importantly by beta-lactam hydrolysis, which breaks down the antibiotic and renders it ineffective.  Inhibitors for one sub-class of beta-lactamase have been developed and successfully applied but no clinically useful inhibitors have been reported to date for the Class B metallo-beta-lactamases (MBLs) and there is a consequent need to develop potent and selective inhibitors for MBLs.

 

An effective solution

Research at the University of Oxford has demonstrated the functionality of a new type of rhodanine based inhibitor, ML302, which selectively targets bacterial MBLs involved in antibiotic resistance.  ML302 undergoes hydrolysis to yield a thioenolate fragment (ML302F), a highly potent broad-spectrum MBL inhibitor.  The thioenolate prevents the MBLs from inactivating beta-lactam based antibiotics by reversibly binding at their active sites.  This compound series could effectively be used to treat various infections by co-application of the inhibitor with a beta-lactam antibiotic, thereby expanding the lifetime of currently used medication.

 

Licensing opportunity

The research is the subject of a Nature Chemistry paper and a patent application has been filed to cover the compound series. Oxford University Innovation welcomes contact from parties interested in licensing this opportunity.  Contact the Technology Transfer Manager by using the link below.

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