Decreased production ofpara-hydroxypenicillin V in penicillin V fermentations |
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Authors: | L T Chang E L McGrory R P Elander D J Hook |
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Institution: | (1) Industrial Division, Bristol-Myers Squibb Company, P.O. Box 4755, 13221-4755 Syracuse, NY, USA;(2) Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Wallingford, CT, USA |
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Abstract: | Summary Penicillin V (phenoxymethyl penicillin) is produced by industrial strains ofPenicillium chrysogenum in the presence of phenoxyacetic acid (POAc), a side-chain precursor for the penicillin V molecule. The wild-type strain ofP. chrysogenum produces an undesirable penicillin byproduct,para-hydroxypenicillin V (p-OH penicillin V), in addition to penicillin V, viapara-hydroxylation of POAc and subsequent incorporation of thep-OH phenoxyacetic acid into the penicillin molecule. Most of thep-OH penicillin V is produced late in cycle when the POAc concentration in the medium is nearly depleted. The level ofp-OH penicillin V produced by the control strain ranges up to 10–15% of the total penicillins produced. 3-Phenoxypropionic acid andp-bromophenylacetic acid partially inhibit the formation ofp-OH penicillin V with a minimal effect on penicillin V productivity. Mutants deficient in their ability to hydroxylate POAc were found to produce lower levels ofp-OH penicillin V. Multi-step mutation and screening, starting with the wild-type strain, have culminated in isolation of mutants which producep-OH penicillin V as 1% of the total penicillins with no adverse effect on penicillin V productivity. |
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Keywords: | Penicillin V fermentation p-Hydroxy penicillin V Hydroxylation phenoxyacetic acid Strain improvement Penicillium chrysogenum |
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