# Recent Advances in the Heterologous Biosynthesis of Natural Products from _Streptomyces_
## 4 Host Engineering Approaches
### Host Cleaning
\begin{table}
\begin{tabular}{c c c c} \hline
**Native Strain** & **Heterologous Host** & **Method Clone** & **Products** \\ \hline _Streptomyces leeuvrehnokii_ C34T & _S. acelicolor_ M1152 and M1154 & PCR, cloning to pJlll0257 & Levepptin [95] \\ \hline _S. varinabilis_ Smt24 & _S. lividans_ SBTS & BAC clone & \multicolumn{1}{c}{Tetramic acid [21]} \\ \hline _Streptomyces kugumenosis_ SCSIO 5802 & _S. coelicolor_ M1152 & \begin{tabular}{c} Phage-PI-derived artificial \\ chromosome (PAC) library \\ \end{tabular} & Neobyssomicin, abyssomicin [96] \\ \hline _Streptomyces_ sp. Acta1362 & _S. albus_ J1074 & \begin{tabular}{c} TR system \\ \end{tabular} & \begin{tabular}{c} Grecocycline [97] \\ \end{tabular} \\ \hline _S. venezudie_ & _S. lividans_ and _S. coelicolor_ & BAC cloning & Pikromycin [22] \\ \hline _S. galtieri_ Sg26 & _S. albus_ J1074 & BAC cloning & Kinamycin [58] \\ \hline _S. albus_ subsp. _chlorinus_ NRRL & _S. albus_ Del14, _S. lividans_ TK24 & BAC clone & Albucidin [57] \\ \hline _S. erythran_ DSM 40517 & _S. acelicolor_ M1152 and M1154 & Direct pathway cloning (DiPaC) & Erythromycin [98] \\ \hline _Streptomyces kugumenosis_ ATCC & _E. coli_ & Co-expression genes & Valinomycin [99] \\ \hline _S. erythran_ & _B. subtilis_ & PCR, cloning & 6-deoxyerythromolide B [\(\%\)] \\ \hline _S. dravanensis_ & _C. glutamicum_ & PCR, cloning & Roseoflavin [87] \\ \hline _S. griseus_ & _P. putida_ & PCR, cloning & Flaviolin [91] \\ \hline _S. kasuganensis_ & _R. erythropolis_ & PCR, cloning & Kasugamycin [94] \\ \hline _Actinsymmen mirum_ DSM 43827 & _S. avemitilis_ SUK22 & PCR, cloning & Mycosporine-glycine-alanine [67] \\ \hline _Kocuria rosea_ s17 & _S. acelicolor_ M1146, _S. sp. s120 & \begin{tabular}{c} Gibson assembly, integration vector \\ pSET152 \\ \end{tabular} & Kocurin [23] \\ \hline _Amycolatopsis_ sp. DEM30355 & _S. acelicolor_ M1152 & PAC library & Vanocressymcin [26] \\ \hline _Myxxococcus xanthus_ DK1622 & _S. albus_ Del14 & PCR and subcloned & Cittills [100] \\ \hline _Actinplanes kinsmensis_ & _S. acelicolor_ M1146 & DNA assembler by yeast & Chuangxinmycin [60] \\ \hline _Kutzneria alluida_ DSM 43870 & _S. albus_ Del14 & BAC vector & Huimycin [62] \\ \hline _Planobisporran_ ATCC 53733 & _S. acelicolor_ M1146 & Cosmid vector & GE2270 [66] \\ \hline _A. mirum_ DSM 43827 & _S. avemitilis_ SUKA22 & \begin{tabular}{c} In vivo by phage \(\lambda\)-Red \\ recombining system \\ \end{tabular} & \begin{tabular}{c} Shinorine, porphyrinx-334, \\ mycosporine-glycine, and \\ mycosporine-glycine-alanine [67] \\ \end{tabular} \\ \hline _Kitasatosporn setae_ KM-6054 & \
\begin{tabular}{c} _Streptomyces leohii_ JCM 14114, \\ _S. griseus_ DSM 2608 \\ \end{tabular} & BAC cloning &
\begin{tabular}{c} Bafilomycins A1, Cl, and B1 \\ (setamycin) [101] \\ \end{tabular} \\ \hline \end{tabular}
\end{table} 
Table 1: List of compounds synthesized heterologously. release from _S. cerevisiae_ that recognizes an 18 bp unique sequence and cleaves DNA for engineering a genome with high efficiency and multiple deletions [111]. This method was successfully applied to delete the red-pigmented undecylprodiginine BGC in _S. coelicolor_ M1141 [111]. Recently, the CRISPR/Cas system of _Streptococcus pyogenes_ (_Sp_Cas9) is a vital tool in genome engineering that is widely applied in different strains [112]. It has been developed and used to clean many _Streptomyces_ hosts, such as _S. coelicolor_, _S. lividans_, and _S. albus_[113, 114]. However, _Sp_Cas9 does not properly work in some _Streptomyces_ strains [115, 116]; therefore, the _Fn_Cas12a system (from _Francisella novicida_ U112), _fn_Cpf1 (from _Francisella tulareis_ subsp. _Invoicida_ U112 Cpf1), _sth_ICas9 (from _Streptococcus thermophilus_ CRISPR1 Cas9), and _sa_Cas9 (from _Staphylococcus aureus_ Cas9) were developed for genome editing _Streptomyces_ strains [116, 117]. For example, the _Fn_Cas12a system was used to disrupt 128 kb of chromosome of _S. hygroscopicus_[117].