IOI scientists find new way to scale-up production of novel antimicrobial drugs
Scientists at the Ineos Oxford Institute for Antimicrobial Research, in collaboration with the Latvian Institute for Organic Synthesis (LIOS), have developed a new process to scale-up production of a novel Metallo-β-Lactamase inhibitor to tackle antibiotic resistance.
Last-resort antibiotics such as carbapenems that are used to treat multi-drug resistant infections are becoming increasingly ineffective due to antimicrobial resistance. Bacteria have become resistant to carbapenems, surviving treatment by producing enzymes called Metallo-β- lactamases (MBLs) that break down antibiotics and prevent them from working.
While bacterial resistance to other drugs can be tackled by co-administrating β-lactam antibiotics and a serine β-lactamase inhibitor, there are currently no clinically approved MBL inhibitors.
Working alongside multiple teams as part of the European-funded ENABLE project, scientists in the IOI have developed a new MBL inhibitor that is being tested in pre-clinical studies. In a newly published paper, researchers explain ways to scale-up its production from small quantities in the lab (milligram quantities), to usable amounts (hundred grams) that can be used in subsequent pre-clinical studies.
This is an exciting step for our MBL drug development work and provides us with excellent findings for follow-on studies. Collaborations such as this with LIOS considerably expand our capabilities. In our labs in Oxford, we routinely make milligram quantities of new inhibitors but to produce material of this complexity on larger scale requires specialist equipment and knowledge of our collaborators.”
The World Health Organisation reports a near static pipeline of antibiotic development despite the urgent need for novel drugs. The IOI and its extensive network of collaborators continue to find solutions to tackle AMR by rapidly developing robust routes that can be scaled-up and provide material of sufficient purity. This ensures that when a new candidate molecule is identified, the subsequent preclinical studies can be expedited, and move the molecule further along the drug development pipeline.
Accessing hundred-gram quantities of our MBL inhibitors after 12 steps is fantastic and successfully developing an industrially relevant synthetic route is a great achievement by the whole team. The stereoselective preparation of the spirocyclic cyclobutane C7 building block is particularly impressive. By working together with collaborators and experts from IOI we can tackle the multifaceted problem of AMR together.”
Read the full paper here: https://pubs.acs.org/doi/10.1021/acs.oprd.3c00002