## 2 Application of Ribosome Engineering to Increase Antibiotic Production
\begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**Antibiotic** & **Strain** & **Method** & **Mutation a ** & **(Fold)/(g/L) b ** & **Year/Ref.** \\ \hline \hline Bacilyin (**25**) & _B. subtilis_ & Str, Rif & K56R L467P & 5–7 (0.0166 \(\pm\) 0.0009) & 2015 [54] \\ \hline Erythromycin (**11**) & _S. erythtraca_ & Rif & S444F & 4 (\(>\)1.5) & 2009 [55] \\ \cline{2-6}  & _S. erythtraca_a ** & Rif & H437R & 4.0 (\(0.163\pm 0.034\)) & 2013 [32] \\ \hline FR900493 (**22**) & _B. cereus_ & Str & - c ** & 7.2 (0.55) & 1998 [33] \\ \cline{2-6}  & _B. cereus_ & Gen & - c ** & 20.7 (0.22) & 2008 [34] \\ \cline{2-6}  & _P. rosea_ & Gen, Str, Rif & - & 1.8 (–) & 2006 [56] \\ \hline \hline Norvancomycin & _A. orientalis_ & Str, Rif, UV, HE & - & 1.4 (–) & 2006 [57] \\ \hline \hline Pyrrolnirtin (**29**) & _P. pyrrocinia_ & Str & - & 10 (0.015) & 1998 [33] \\ \cline{2-6}  & _P. pyrrocinia_ & Gen & - & 5.3 (0.008) & 2008 [34] \\ \hline \hline Vanomycin (**8**) & _A. orientalis_ & Rif & S442Y & 2.6–3.4 (0.27 \(\pm\) 0.017) & 2013 [32] \\ \hline Violacein (**24**) & _E. coli_ & Lin, Kan, HE & - & 41 (–) & 2011 [58] \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Summary of non-_Streptomyces_ mutant effective for antibiotic overproduction. \begin{table}
\begin{tabular}{c c c c c c} \hline \hline
**Antibiotic** & **Strain** & **Method** & **Mutation a ** & **(Fold)/(g/L) b ** & **Year/Ref. ** \\ \hline \hline Avermectins (**3.4**) & _S. auridchromogenes_ & _Fir_ overexpression & - & 3-3.7 (\(>\)0.8) & 2010 [35] \\ Avilamycin (5) & _S. uridchromogenes_ & \({}^{60}\)Co y-ray, GS, Str & K43N & 36.8 (1.4) & 2013 [36] \\ Chloramphenicol (**21**) & _S. ocelicolor_ & Str, Rif, HE & - & 20–40 (–) & 2011 [37] \\ Congodicine & _S. ocelicolor_ & Str, Rif, HE & - & 20–40 (–) & 2011 [37] \\ \hline Daptomycin (**7**) & _S. rosesporus_ & Ple & - & 1.3 (\(>\)0.08) & 2013 [38] \\  & _S. rosesporus_ & Neo, Gen, Rif, Par, GS a ** & - & 4 (0.324) & 2018 [39] \\ \hline A21978C & _S. rosesporus_ & Str, Reporter gene & K43N & 2.2 (\(>\)0.12) & 2012 [40] \\ \hline Formycin A (**28**) & _S. lueendulae_ & Str & - & 5.2 (0.13) & 1998 [33] \\  & _S. lueendulae_ & Str & R440H & 2.4–4.6 (0.055 \(\pm\) 0.014) & 2013 [32] \\ \hline Fredericamycin A (**15**) & _S. chattanoogensis_ & Str & - & 26 (0.26) & 1998 [33] \\  & _S. somalensis_ & Rif & R444H & 3 (0.6795 \(\pm\) 0.0158) & 2015 [41] \\ \hline Milbemycin (**19.20**) & _S. hinghen  
Enediynes are the most cytotoxic natural products known to date, and they are excellent payloads for antibody-drug conjugates against various cancers. Tiancimycins were recently discovered as 10-membered anthraquinone-type enediynes (Figure 3) [47]. The yield of tiancimycins in the wild-type _Streptomyces_ sp. CB03234 was below 1 mg/L, which significantly hampered preclinical studies using this strain. A _rif_ strain CB03234-R-16 and a _str_ strain CB03234-S were obtained by treating the \(S\). sp. CB03234 wild-type strain with rifampicin or streptomycin [48; 49]. The CB03234-R-16 has an _rpoB_ L422P mutation, while CB03234-S has an _rpsL_ K43N mutation. The yield of tiancimycin A (**17**) in CB03234-R-16 was \(22.5\pm 3.1\) mg/L in shaking flasks and \(13\pm 1\) mg/L in 15-L fermentors. The yield of tiancimycin A (**17**) in CB03234-S reached \(13.7\pm 0.3\) mg/L in 25-L fermentors. Interestingly CB03234-S produced tiancimycin D (**14**), an analog of tiancimycin A (**17**), with a decent yield of \(19.2\pm 0.4\) mg/L. The increase in the production of these promising anticancer drug leads would provide ample compounds for the future preclinical study.