Interrogation of Streptomyces avermitilis for efficient production of avermectins

Abstract

The 2015 Nobel Prize in Physiology or Medicine has been awarded to avermectins and artemisinin, respectively. Avermectins produced by Streptomyces avermitilis are excellent anthelmintic and potential antibiotic agents. Because wild-type strains only produce low levels of avermectins, much research effort has focused on improvements in avermectin production to meet the ever increasing demand for such compounds. This review describes the strategies that have been widely employed and the future prospects of synthetic biology applications in avermectin yield improvement. With the help of genome sequencing of S. avermitilis and an understanding of the avermectin biosynthetic/regulatory pathways, synthetic and systems biotechnology approaches have been applied for precision engineering. We focus on the design and synthesis of biological chassis, parts, devices, and modules from diverse microbes to reconstruct and optimize their dynamic processes, as well as predict favorable effective overproduction of avermectins by a 4Ms strategy (Mine, Model, Manipulation, and Measurement).

Toward Systems Metabolic Engineering of Streptomycetes for Secondary Metabolites Production

“…Some noteworthy examples include the production of tacrolimus (FK506) using Streptomyces tsukubaensis, [67][68][69] ascomycin (FK520) using Streptomyces hygroscopicus var. ascomyceticus, [70][71][72] avermectin using S. avermitilis, [73] and pristinamycin I (PI) and II (PII) using Streptomyces pristinaespiralis. [74,75] To solve the issue of low production yield of tacrolimus in the natural producer, Wang et al [67] first determined the intracellular response of S. tsukubaensis to exogenous feeding of four precursors known to promote the tacrolimus biosynthesis.…”

“…[73] As avermectin biosynthesis is under the tight control of several regulators, much focus has been put on relieving such regulators. The pathway-specific regulator AveR, which is involved in the activation of avermectin biosynthesis, is itself subject to both negative and positive regulation.…”

“…The pathway-specific regulator AveR, which is involved in the activation of avermectin biosynthesis, is itself subject to both negative and positive regulation. [73] Here, the two TetR family transcriptional regulators (TFRs) encoded by the genes SAV576 and SAV577 were found to indirectly downregulate the avermectin biosynthesis through binding to the promoter region of SAV575; SAV575 is known to be involved in providing acetate and propionate extender units required for the avermectin production. [76,77] Using a combination of microarray analysis, www.advancedsciencenews.com www.biotechnology-journal.com Table 1.…”

“…Increasing flux through precursor pathways 3-fold [73,76,77] Microarray analysis and ChIP assays for the analysis of expression levels…”

Different fates of avermectin and artemisinin in China

“…Professors Wensheng Xiang and Zhongjun Qin made significant contributions on the research and development of doramectin. Through collective efforts, researchers at the Institute of Microbiology Chinese Academy of Sciences (IMCAS) and their collaborators increased the production of avermectin B1a with a titer to 9 g L 1 and lowered the market price by forty times (Chen et al, 2016). In April 2010, the avermectin industrial alliance (AIA) composed of thirteen avermectin manufacturers was established.…”