Conclusions
In the present study, we re-sequenced the whole genome of an
erythromycin overproducer S. erythraea HL3168 E3 and carried out
comparative genomic and transcriptomic analysis of E3 with respect to
the wild type NRRL23338. Genomic variations occurred in E3 in terms of
gene transposition, fragment deletions in 56 sequences and 255 SNPs,
which were partly distinguished from a previous E3 genome obtained via
pyrosequencing (Y. Li et al., 2013). Comparative omics analysis revealed
that the phenotypic difference between E3 and NRRL23338 resulted mainly
from genomic and transcriptomic changes in central carbon and nitrogen
metabolism, biosynthesis of secondary metabolites, and cofactor
metabolism.
Within transcriptomic analysis the top ranking reporter metabolites were
L-glutamine/L-glutamate and 2-oxoglutarate, which pointed to the
important role of nitrogen metabolism and the signal transduction in the
biosynthesis of erythromycin. Genes coding for direct regulators of
erythromycin biosynthesis gene cluster i.e. BldD and PhoP in E3 were not
stimulated, we predicted that the regulatory networks of erythromycin
BGC in E3 might be different from our anticipation. Expression of genes
involved in the TCA cycle, ED pathway and the degradation of fatty acid
changed in E3, which facilitated to supply more precursors for the
biosynthesis of erythromycin. Moreover, several genes involved in
biosynthesis of secondary metabolites other than erythromycin were
expressed at extremely low levels in E3, which addressed the importance
of construction of super-producer through genome minimization (Peano et
al., 2007).
Based on the omics analysis, we proposed putative mechanisms by which E3
boosted the biosynthesis of erythromycin. The mechanisms provided
molecular targets to strengthen the productivity of erythromycin by E3.
As an example, we enhanced the supply of erythromycin precursors by
manipulating targets derived from one of the proposed mechanisms. The
overexpression of sucBA resulted in an enhancement of the
erythromycin titer by 71% in E3. The present study showed that
comparative omics analysis could reveal the differences between the
physiologies of wild type strains and their overproducing derivatives,
and also point out strategies for enhancing the production of secondary
metabolites in overproducers even further.