## 1 Introduction  
Streptomyces are proficient producers of bioactive natural products, such as antibiotics (streptomycin and daptomycin), anticancer agents (bleomycin and doxorubicin), immunosuppressive (rapamycin), and agents used in veterinary medicine and agriculture (avermectins and spinosyn) [1; 2; 3]. Many _Streptomyces_ natural products or their derivatives are also essential tools to discover new biology [4]. Rapamycin, a macrocyclic polyketide discovered from _Streptomyces hygroscopic_ in 1972, simultaneously binds FKBP12 and the mammalian target of rapamycin (mTOR) [5]. These studies led to the discovery of mTOR complex 1 and mTOR complex 2, which regulate protein synthesis or cellular metabolism in mammalian cells [6]. Several rapalogs, derivatives of the parent rapamycin, are useful in the treatment of renal cell carcinoma [7]. Rapamycin-inspired macrocycles recently became drug leads for the treatment of kidney ischaemia reperfusion injury [8]. The genome sequences of _Streptomyces__avernitidis_ and _Streptomyces__colicolor_ A3(2) reveal that they contain 25 or 22 biosynthetic gene clusters (BGCs), respectively [9; 10]. These surprising findings at the beginning of the 21 st century suggest that most BGCs are silent under standard culture conditions and that there is a huge biosynthetic potential in the genus of _Streptomyces_. Since there are over 11,500 actinobacterial genomes listed in the Joint Genome Institute genome databases and the Genbank, the current discovered natural products from _Streptomyces_ or _Actinomyces_ are only the tip of an iceberg [11; 12; 13]. In addition, 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 daumorubicin [14] (Figures 1 and 2). The shortage of these medicines could precipitate a major public health crisis in any modern society. Ribosome engineering is an approach to discover microbes with certain spontaneous mutations in their ribosome or RNA polymerase, through screening antibiotic-resistant mutants on Petri dishes. Some selected mutants may have elevated secondary metabolite production or produce new series of natural products with interesting biological activities. [PERSON] and co-workers discovered a streptomycin-resistant TK24 strain in the study of the model _Streptomyces_ strain _Streptomyces_ _lividans_ in 1996 [15]. This natural mutant has a K88N mutation in the _rpsL_ gene, which encodes ribosomal protein S12 and produces the well-studied blue pigment antibiotic actinorodin (Act) (**23**). They and others were subsequently able to use a streptomycin screen to discover other mutations in _rpsL_ in different _Streptomyces_ strains. Rifampicin was later used to screen for mutants with elevated secondary metabolite production and spontaneous mutation in the _rpoB_ gene encoding the RNA polymerase \(\beta\) subunit. Apart from mutations conferring resistance to streptomycin or rifampicin, other antibiotics, such as gentamicin, paromomycin, geneticin, fusidic acid, thiostrepton, and limomycin, have also been successfully applied to screen for mutants with elevated levels of secondary metabolite production. In the past two decades, this approach has been widely used for increasing the production of bioactive molecules in many bacterial species and for activating silent or poorly expressed BGCs in the post-genomic era. Recently, there have been several excellent reviews to discuss various aspects of ribosome engineering and synthetic biology approaches to engineer cellular metabolism [16; 17; 18]. In this short review, we focus on the discussion of the applications and mechanism of ribosome engineering to natural product discovery and yield improvement in _Streptomyces_.