Novel octaketide macrolides related to 6-deoxyerythronolide B provide evidence for iterative operation of the erythromycin polyketide synthase

Background: The macrolide antibiotic erythromycin A, like other complex ali phatic polyketides, is synthesised by a bacterial modular polyketide syntha se (PKS). Such PKSs, in contrast to other fatty acid and polyketide synthas es which work iteratively, contain a separate set or module of enzyme activ ities for each successive cycle of polyketide chain extension, and the numb er and type of modules together determine the structure of the polyketide p roduct. Thus, the six extension modules of the erythromycin PKS (DEBS) toge ther catalyse the production of the specific heptaketide 6-deoxyerythronoli de B. Results: A mutant strain of the erythromycin producer Saccharopolyspora ery thraea, which accumulates the aglycone intermediate erythronolide B, was fo und unexpectedly to produce two novel octaketides, both 16-membered macroli des. These compounds were detectable in fermentation broths of wild-type S. erythraea, but not in a strain from which the DEBS genes had been specific ally deleted. From their structures, both of these octaketides appear to be aberrant products of DEBS in which module 4 has 'stuttered', that is, has catalysed two successive cycles of chain extension. Conclusions: The isolation of novel DEBS-derived octaketides provides the f irst evidence that an extension module in a modular PKS has the potential t o catalyse iterative rounds of chain elongation like other type I FAS and P KS systems. The factors governing the extent of such 'stuttering' remain to be determined.