Abstract
The first antibiotic-producing actinomycete (Streptomyces antibioticus) was described by Waksman and Woodruff in 1940. This discovery initiated the “actinomycetes era”, in which several species were identified and demonstrated to be a great source of bioactive compounds. However, the remarkable group of microorganisms and their potential for the production of bioactive agents were only partially exploited. This is caused by the fact that the growth of many actinomycetes cannot be reproduced on artificial media at laboratory conditions. In addition, sequencing, genome mining and bioactivity screening disclosed that numerous biosynthetic gene clusters (BGCs), encoded in actinomycetes genomes are not expressed and thus, the respective potential products remain uncharacterized. Therefore, a lot of effort was put into the development of technologies that facilitate the access to actinomycetes genomes and activation of their biosynthetic pathways. In this review, we mainly focus on molecular tools and methods for genetic engineering of actinomycetes that have emerged in the field in the past five years (2015–2020). In addition, we highlight examples of successful application of the recently developed technologies in genetic engineering of actinomycetes for activation and/or improvement of the biosynthesis of secondary metabolites.
Highlights
Actinomycetes are Gram-positive, mostly aerobic, filamentous bacteria of the phylumActinobacteria [1,2,3,4]
The main difference between the replicative and integrative plasmids is the fact that replicative plasmids contain origins of replication and are able to multiply in the host cell, while integrative plasmids harbor integrases and sequences which facilitate their integration into the actinomycete0 s chromosome
In contrast to the native strain S. griseus, heterologous hosts harboring the refactored gene cluster produced the polycyclic tetramate macrolactam (PTM) and the production yields were increased [144] compared to a previously described F60 construction [145]. These results suggest that the identified promoters may be widely applicable in synthetic biology platforms for activation of silent natural product biosynthetic pathways and characterization and/or optimization of already expressed biosynthetic gene clusters (BGCs) in actinomycetes strains
Summary
Actinobacteria [1,2,3,4] They were initially regarded as organisms, which share morphological characteristics with both bacteria and fungi [5,6] and they were considered as transitional forms between the two groups. Age” of antibiotic discovery (1940s–1960s), several antimicrobial and other valuable compounds were discovered from actinomycetes Many of these molecules have been developed to commercial products, including agrochemicals and pharmaceuticals [14,47,48,49,50,51]. Since the whole genome sequencing of the first actinomycetes, which was the genome of Streptomyces coelicolor A3 [52], hundreds actinomycetes genomes were sequenced and annotated These data revealed that the genomes encode several biosynthetic gene clusters (BGCs) for the production of diverse secondary metabolites. (meta)genomics-based approaches as well as modern metabolomics-inspired technologies were highlighted in other reviews [43,45,46,61,62,63,64,65,66,67,68], this review provides the reader with an overview on recent advances in molecular tools for the genetic engineering of actinomycetes
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