Direct Fermentation of Deacetylcephalosporin C

Dr J. Basch, Bristol-Meyers Squibb, USA

Dr Basch presented work carried out at BMS to improve the overall yield of Cephalosporin C (Ceph-C) in the fermentation of Acremonium chrysogenum. Significant amounts of Ceph-C are lost by non-enzymatic degradation under the fermentation conditions (pH 4-7) to compound X. This can be minimised by stabilising the Cephalosporin nucleus by converting Ceph-C to deacetylCeph-C.

This conversion can be achieved by adding Rhodosporidium toruloides whole cells to the fermentation and results in the accumulation of deacetylCeph-C. However this also requires additional fermentation to produce R. toruloides and extra downstream processing. But this problem was overcome by cloning the gene for the active ester (Ceph-C esterase) and then using it to modify A. chrysogenum.

The final hurdle is to convert deacetylCeph-C in to Ceph-C and this can be achieved either chemically using isopropenyl acetate / dicyclohexylamine or biochemically using Cephalosporin C esterase with isopropenyl acetate. Overall the direct fermentation of Deacetylcephalosporin C results in a 35-40% increase in the Cephalosporin nucleus recovered from the fermentation broth of A. chrysogenum.