Comparative genomic and transcriptomic analysis guides to further enhance the biosynthesis of erythromycin by an overproducer

Abstract

Omics approaches have been applied to understand the boosted productivity of natural products by industrial high-producing microorganisms. Here, with the updated genome sequence and transcriptomic profiles derived from highthroughput sequencing, we exploited comparative omics analysis to further enhance the biosynthesis of erythromycin in an industrial overproducer, Saccharopolyspora erythraea HL3168 E3. By comparing the genome of E3 with the wild type NRRL23338, we identified fragment deletions inside 56 coding sequences and 255 single-nucleotide polymorphisms over the genome of E3. A substantial number of genomic variations were observed in genes responsible for pathways which were interconnected to the biosynthesis of erythromycin by supplying precursors/ cofactors or by signal transduction. Furthermore, the transcriptomic data suggested that genes involved in the biosynthesis of erythromycin were significantly upregulated constantly, whereas some genes in biosynthesis clusters of other secondary metabolites contained nonsense mutations and were expressed at extremely low levels. Through comparative transcriptomic analysis, L-glutamine/ L-glutamate and 2-oxoglutarate were identified as reporter metabolites. Around the node of 2-oxoglutarate, genomic mutations were also observed. Based on the omics association analysis, readily available strategies were proposed to engineer E3 by simultaneously overexpressing sucB (coding for 2-oxoglutarate dehydrogenase E2 component) and sucA (coding for 2-oxoglutarate dehydrogenase E1 component), which increased the erythromycin titer by 71% compared to E3 in batch culture. This study provides more promising molecular targets to engineer for enhanced production of erythromycin by the overproducer.

Mechanistic insight for improving butenyl-spinosyn production through combined ARTP/UV mutagenesis and ribosome engineering in Saccharopolyspora pogona

“…Omics analysis has proven invaluable in elucidating the intricacies of intracellular metabolism and regulatory networks in microbial strains. Li et al further improve the production of erythromycin in mutagenesis-derived high-yield strains through comprehensive omics analysis ( Li et al, 2022 ). Wang et al employed a multi-omics analysis to uncover the intracellular triacylglycerol (TAG) metabolic regulation ( Wang et al, 2020 ).…”

“…Butenyl-spinosyn, produced in the actinomycete Saccharopolyspora pogona ( S. pogona ), has a similar macrolide structure to spinosyn and thus exhibits insecticidal, acaricidal, and parasiticide activities ( Li et al, 2022 ; Rang et al, 2022 ). Compared to spinosyn, butenyl-spinosyn possesses a wider insecticidal spectrum and it is more environmentally sustainable than spinosyn ( Rang et al, 2020 ; He et al, 2021a ).…”

Genome-wide identification and analysis of bZIP gene family reveal their roles during development and drought stress in Wheel Wingnut (Cyclocarya paliurus)

“…This may explained by the transcriptomic data obtained from four sub-genomes in autotetraploid C. paliurus and the lack of bZIP domain validation. In addition, compared to the genes predicted from transcriptomic data, genome-wide identification combined with a transcriptomic analysis can provide more information on gene structures, functions, and expression patterns [ 36 , 37 ]. Further chromosome-level assemblies of the four sub-genomes may facilitate more comprehensive functional studies of bZIP genes and their regulatory mechanisms in C. paliurus .…”

Enhancing erythromycin production in Saccharopolyspora erythraea through rational engineering and fermentation refinement: A Design‐Build‐Test‐Learn approach

“…[ 4 ] While various instances have showcased the effectiveness of mutagenesis and screening methods, the underlying mechanisms through which industrial actinobacteria augment yields or synthesize desired metabolites largely remain enigmatic. [ 5 ]…”

“…[4] While various instances have showcased the effectiveness of mutagenesis and screening methods, the underlying mechanisms through which industrial actinobacteria augment yields or synthesize desired metabolites largely remain enigmatic. [5] Erythromycin, a prominent constituent of the macrolide antibiotic class, has been established as a vital therapeutic agent for addressing diverse infections attributed to Gram-positive bacteria. [6] The spotlight has turned to a succession of erythromycin derivatives, encompassing azithromycin, roxithromycin, and clarithromycin.…”