Abstract
Microbial natural product drug discovery and development has entered a new era, driven by microbial genomics and synthetic biology. Genome sequencing has revealed the vast potential to produce valuable secondary metabolites in bacteria and fungi. However, many of the biosynthetic gene clusters are silent under standard fermentation conditions. By rational screening for mutations in bacterial ribosomal proteins or RNA polymerases, ribosome engineering is a versatile approach to obtain mutants with improved titers for microbial product formation or new natural products through activating silent biosynthetic gene clusters. In this review, we discuss the mechanism of ribosome engineering and its application to natural product discovery and yield improvement in Streptomyces. Our analysis suggests that ribosome engineering is a rapid and cost-effective approach and could be adapted to speed up the discovery and development of natural product drug leads in the post-genomic era.
Highlights
Streptomycetes are proficient producers of bioactive natural products, such as antibiotics, anticancer agents, immunosuppressants, and agents used in veterinary medicine and agriculture [1,2,3]
A macrocyclic polyketide discovered from Streptomyces hygroscopicus in 1972, simultaneously binds FKBP12 and the mammalian target of rapamycin [5]
Addition, biology there is aapproaches huge need totoincrease thecellular yield of metabolism many approved natural ribosome andInsynthetic engineer. In this products-based drugs, and many of them are on the list of essential medicines recommended by the short review, we focus on the discussion of the applications and mechanism of ribosome engineering to Organization, suchimprovement as the antibiotics vancomycin, streptomycin, ivermectin, the natural product discovery and yield in Streptomyces
Summary
Streptomycetes are proficient producers of bioactive natural products, such as antibiotics (streptomycin and daptomycin), anticancer agents (bleomycin and doxorubicin), immunosuppressants (rapamycin), and agents used in veterinary medicine and agriculture (avermectins and spinosyn) [1,2,3]. There is a huge need to increase the yield of many approved natural products-based drugs, and many of them are on the list of essential medicines recommended by the World Health Organization, such as the antibiotics vancomycin, streptomycin, and ivermectin, the semisynthetic derivative of avermectins, as well as antitumor agents bleomycin, dactinomycin, and daunorubicin [14] (Figures 1 and 2). The shortage of these medicines could precipitate a major public health crisis in any modern society.
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