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).
Keywords: APGD, atmospheric pressure glow discharge; Avermectins; BCDH, branched-chain alpha-keto acid dehydrogenase; ChIP, chromatin immunoprecipitation; DO, dissolved oxygen; EER, ethanol evolution rate; GBL, gamma-butyrolactone; HMGE, high-magnet gravitational environment; IB-CoA, isobutyryl-CoA; MB-CoA, 2-methybutyryl-CoA; MDR-TB, multidrug-resistant tuberculosis; MM-CoA, methylmalonyl- CoA; MMS, methyl methanesulphonate; MRSA, methicillin-resistant Staphylococcus aureus; MTP, microtiter plates; Metabolic engineering; NA, nitrous acid; NTG, N-methyl-N-nitro-N-nitrosoguanidine; OUR, oxygen uptake rate; PBD, Plackett–Burman design; RF, radio frequency; RRF, ribosome recycling factor; SAM, S-adenosylmethionine; STPK, serine-threonine protein kinases; Streptomyces avermitilis; Synthetic biology; TAR, transformation-assisted recombination; UV, ultraviolet rays; XDR-TB, extensively drug-resistant tuberculosis.