A new fermentation process for β-lactam antibiotics

Carbapenem intermediate

A novel procedure for the preparation of β-lactams, from non-natural substrates.

Many β-lactam antibiotics are from the cephalosporin and penicillin families. Some of these are produced directly by fermentation, while other sub-families, including the carbapenems, are produced by total synthesis. The high production costs of antibiotics produced by total synthesis, not only limits their use, but also precludes development of new compounds.

The preparation of carbapenems often involves a key intermediate that contains a substituted β-lactam ring. This can only be obtained by means of chemical synthesis; no fermentation route currently exists to this, or any alternative common intermediate.

β-Lactam synthetase is known to catalyae β-lactam ring formation, from an acyclic precursor during the biosynthesis of clavulanic acid; this is clinically used to enhance antibiotic performance. The Oxford Invention shows for the first time, that recombinant wild-type β-lactam synthetase not only accepts non-natural substrates, but also converts them to substituted β-lactams.

The Oxford Invention provides, for the first time, a method for developing a fermentation route to key β-lactam intermediates. It is expected that this will deliver significant cost savings by comparison with current synthetic processes and may aid the development of novel antibiotics.

Commercialisation opportunity

The invention is the subject of an international patent application. Isis Innovation Limited is in a position to offer this invention for licensing to a commercial partner.