Comparative Genomic and Regulatory Analyses of Natamycin Production of Streptomyces lydicus A02

Abstract

Streptomyces lydicus A02 is used by industry because it has a higher natamycin-producing capacity than the reference strain S. natalensis ATCC 27448. We sequenced the complete genome of A02 using next-generation sequencing platforms, and to achieve better sequence coverage and genome assembly, we utilized single-molecule real-time (SMRT) sequencing. The assembled genome comprises a 9,307,519-bp linear chromosome with a GC content of 70.67%, and contained 8,888 predicted genes. Comparative genomics and natamycin biosynthetic gene cluster (BGC) analysis showed that BGC are highly conserved among evolutionarily diverse strains, and they also shared closer genome evolution compared with other Streptomyces species. Forty gene clusters were predicted to involve in the secondary metabolism of A02, and it was richly displayed in two-component signal transduction systems (TCS) in the genome, indicating a complex regulatory systems and high diversity of metabolites. Disruption of the phoP gene of the phoR-phoP TCS and nsdA gene confirmed phosphate sensitivity and global negative regulation of natamycin production. The genome sequence and analyses presented in this study provide an important molecular basis for research on natamycin production in Streptomyces, which could facilitate rational genome modification to improve the industrial use of A02.

Phosphate effect on filipin production and morphological differentiation in Streptomyces filipinensis and the role of the PhoP transcription factor

“…lividans and S . lydicus Δ phoP mutants is also sensitive to high Pi concentrations [22,33,34], thus it seems likely that a yet unidentified PhoP-independent mechanism blocks antibiotic biosynthesis under excess phosphate conditions.…”

“…natalensis and S . lydicus overproduce pimaricin [33,34], and S . avermitilis overproduces avermectin [35].…”

Identification of a gene from Streptomyces rimosus M527 negatively affecting antibiotic biosynthesis and morphological differentiation

“…The nsdA gene, which is found and conserved in some Streptomyces, negatively affects morphological differentiation and secondary metabolite production [7][8][9]. Recently, by genome mining of S. rimosus M527, the nsdA homologue nsdA sr was found, which encodes a 491-amino-acid protein that shares up to 75% amino acids with other NsdA proteins.…”

“…Subsequent studies report that nsdA negatively affects antibiotic biosynthesis and morphological differentiation in Streptomyces. For example, in Streptomyces bingchengensis and Streptomyces lydicus A02, disruption of nsdA caused increased production of secondary metabolites (milbemycin A4, nanchangmycin, and natamycin, along with greater production of pigment and spores than their wildtype strain [8,9].…”

Enhanced natamycin production by co-expression of Vitreoscilla hemoglobin and antibiotic positive regulators in Streptomyces gilvosporeus

“…Species of soil-dwelling actinobacteria belonging to the family Streptomycetaceae are widespread in nature and are well-known for their ability to produce a large number of antibiotics and other secondary metabolites that are immensely beneficial to humans [1]. Natamycin, also known as pimaricin, is a macrolide antifungal antibiotic containing a 26-member tetraene moiety which is produced by a number of Streptomyces species such as S. natalensis [2], S. gilvosporeus [3], S. chattanoogensis [4] and S. lydicus [5][6][7]. Owing to its broad-spectrum antifungal activity and low toxicity to mammalian cells, natamycin is widely used as an antifungal agent in the food industry as well as in medicine [8].…”