Comparative Genomics Determines Strain-Dependent Secondary Metabolite Production in Streptomyces venezuelae Strains

Abstract

Streptomyces venezuelae is well known to produce various secondary metabolites, including chloramphenicol, jadomycin, and pikromycin. Although many strains have been classified as S. venezuelae species, only a limited number of strains have been explored extensively for their genomic contents. Moreover, genomic differences and diversity in secondary metabolite production between the strains have never been compared. Here, we report complete genome sequences of three S. venezuelae strains (ATCC 10712, ATCC 10595, and ATCC 21113) harboring chloramphenicol and jadomycin biosynthetic gene clusters (BGC). With these high-quality genome sequences, we revealed that the three strains share more than 85% of total genes and most of the secondary metabolite biosynthetic gene clusters (smBGC). Despite such conservation, the strains produced different amounts of chloramphenicol and jadomycin, indicating differential regulation of secondary metabolite production at the strain level. Interestingly, antagonistic production of chloramphenicol and jadomycin was observed in these strains. Through comparison of the chloramphenicol and jadomycin BGCs among the three strains, we found sequence variations in many genes, the non-coding RNA coding regions, and binding sites of regulators, which affect the production of the secondary metabolites. We anticipate that these genome sequences of closely related strains would serve as useful resources for understanding the complex secondary metabolism and for designing an optimal production process using Streptomyces strains.

Re-classification of Streptomyces venezuelae strains and mining secondary metabolite biosynthetic gene clusters

“…To date, 29 Streptomyces have been categorized as S. venezuelae strains on the basis of the similarity in their morphology and carbon utilization ( Ehrlich et al., 1948 ; Probst et al., 1965 ; Kim et al., 2020 ). In order to reassess this classification, we first compared phenotypic characteristics of ten S. venezuelae strains commercially available from ATCC (listed in Table 1 ).…”

“…On average, approximately 30 secondary metabolite biosynthetic gene clusters (smBGCs) are encoded in each Streptomyces genome, and most of these smBGCs are species-specific ( Omura et al., 2001 ; Bentley et al., 2002 ). Moreover, recent genome mining studies have shown high chemical diversity even within closely related Streptomyces strains ( Seipke, 2015 ; Antony-Babu et al., 2017 ; Park and Andam, 2019 ; Sottorff et al., 2019 ; Belknap et al., 2020 ; Kim et al., 2020 ), thereby emphasizing the importance of genome mining at the strain level.…”

“…First, taxonomically close strains or species are likely to possess similar smBGCs, conserved regulatory systems, and common precursors from a primary metabolism ( Zakrzewski et al., 2012 ; Romero-Rodriguez et al., 2015 ; Xu et al., 2019 ). Therefore, utilization of an accurate phylogenetic analysis is vital in comparative genomics to identify genetic factors that influence the secondary metabolites production and host selections for heterologous expressions ( Cho et al., 2019 ; Myronovskyi and Luzhetskyy, 2019 ; Kim et al., 2020 ). Second, misclassified Streptomyces strains produce distinct pools of secondary metabolites ( Doroghazi and Metcalf, 2013 ).…”

“…Among a total of 29 S. venezuelae strains that have been isolated to date, S. venezuelae ATCC 10712 has been extensively studied with regard to secondary metabolite production and developmental regulation. The strain has been noted to produce chloramphenicol for the treatment of bacterial infections ( Vitayakritsirikul et al., 2016 ), and jadomycin exhibiting antimicrobial activities and breast cancer cytotoxicity ( Kim et al., 2020 ). Also, S. venezuelae ATCC 15439 encodes the pikromycin BGC, which has been extensively studied because of its unique ability to produce diverse macrolides from one cluster ( Xue et al., 1998 ).…”

Recent Advances of Actinomycetes

“…The study by W. Kim et al [6] explores complete genome sequences of three S. venezuelae strains (ATCC 10712, ATCC 10595, and ATCC 21113) harboring chloramphenicol and jadomycin BGCs. The high-quality genome sequences exhibited that the three strains share more than 85% of total genes, including most of the SM BGCs.…”