Production of the antitumor drug epirubicin (4'-epidoxorubicin) and its precursor by a genetically engineered strain of Streptomyces peucetius.
A fermentation method that bypasses the low-yielding semisynthesis of epirubicin (4'-epidoxorubicin) and 4'-epidaunorubicin, important cancer chemotherapy drugs, has been developed for Streptomyces peucetius. This bacterium normally produces the anthracycline antibiotics, doxorubicin and daunorubicin; the 4'-epimeric anthracyclines are formed by introducing the heterologous Streptomyces avermitilis avrE or Saccharopolyspora eryBIV genes into an S. peucetius dnmV mutant blocked in the biosynthesis of daunosamine, the deoxysugar component of these antibiotics. Product yields were enhanced considerably by replacing the chromosomal copy of dnmV with avrE and by introducing further mutations that can increase daunorubicin and doxorubicin yields in the wild-type strain. This method demonstrates that valuable hybrid antibiotics can be made by combinatorial biosynthesis with bacterial deoxysugar biosynthesis genes.
Madduri
K
K
School of Pharmacy, University of Wisconsin, Madison 53706, USA.
Kennedy
J
J
Rivola
G
G
Inventi-Solari
A
A
Filippini
S
S
Zanuso
G
G
Colombo
A L
AL
Gewain
K M
KM
Occi
J L
JL
MacNeil
D J
DJ
Hutchinson
C R
CR
D000903:Antibiotics, Antineoplastic / Q000096:biosynthesis*; D017931:DNA Primers; D015251:Epirubicin / Q000096:biosynthesis*; D005285:Fermentation; D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial; D005818:Genetic Engineering; D005838:Genotype; D006595:Hexosamines / Q000096:biosynthesis; D009154:Mutation / Q000235:genetics; D010957:Plasmids; D011355:Prodrugs / Q000378:metabolism*; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism*
D000903:Antibiotics, Antineoplastic; D017931:DNA Primers; D006595:Hexosamines; D011355:Prodrugs; C007217:daunosamine; D015251:Epirubicin