Synthesis of Deactoxycephalosporin C by a Mutant of Cephalosporium acremonium

Abstract

A number of Cephalosporium acremonium mutants blocked in the synthesis of cephalosporin C were investigated for accumulation of other ,3-lactam compounds. The non-cephalosporin C producers were isolated after exposing the superior cephalosporin C-producing strain M8650-4 to ultraviolet light (268 nm). One of the blocked mutants, MH63, accumulated deacetylcephalosporin C (0.4 mg/ml), deacetoxycephalosporin C (1.5 mg/ml), and penicillin N (2.7 mg/ml). In contrast, the parent of MH63 produced high levels of cephalosporin C as well as deacetylcephalosporin C (2.2 mg/nal) and penicillin N (1.0 mg/ml), but only traces of deacetoxycephalosporin C (about 0.1 mg/ml). Deacetoxycephalosporin C was isolated from the mutant strain and identified by ultraviolet light, nuclear magnetic resonance, bioactivity spectrum, and co-migration with authentic standard in three chromatography systems.

Natural Beta-Lactam Antibiotics

“…Mutants blocked in the fi nal steps in cephalosporin biosynthesis were isolated. Some of them accumulated deace tylcephalosporin C (42, 45), and others were found to accumulate deacetox ycephalosporin C (44,107) in the fermentation broths. Cell-free extract of the parent strain converted deacetoxycephalosporin C into cephalosporin C, but extracts of the blocked mutants were incapable of this conversion (41,43).…”

“…For a long time only a few strains of molds had been known to produce ceph alosporin C. Recent studies using ,8-lactam-super-susceptible mutants of bacteria (72,74,77) have demonstrated, however, that a considerable num ber of genera of eukaryotic fungi other than Cephalosporium or Emericel [opsis produce cephalosporin C and related compounds. Reports are accumulating on the fermentation production of cephem compounds by wild isolates and also by mutant organisms derived from cephalosporin C-producing strains (42,52,66,68,73,107,121) (Table 2). Production of cephalosporins from n-paraffin was also reported (75).…”

Microbial Culture Selection

“…Mutation and medium manipulation with the nebramycin-producing organism Streptomyces tenebrarius, a culture producing a number of nebramycin components, yielded a variety of strains, some of which elaborated a single component in fermentations (Stark et al, 1971). In a series of mutants which were blocked in the synthesis of cephalosporin C, strains were encountered which synthesized enhanced levels of deacetoxycephalosporin C as well as deacetylcephalosporin C (Queener et al, 1974). Streptomyces noursei produces cycloheximide and the unrelated metabolite, nystatin.…”

Genetics of antibiotic production.

“…All CPCmutants (102,104,105,179,241) fall into three classes, accumulating PCN, DOCPC, and DCPC; PCN and DOCPC; or PCN only. This is consistent with a linear biosynthetic pathway: PCN -+ DOCPC --CPC.…”