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\begin{document}

\title{Medium optimization and subsequent fermentative regulation for the
scaled-up production of anti-tuberculosis drug leads ilamycin-E1/E2}



\author[1]{Zhiying Fan}%
\author[1]{Nian Tong}%
\author[1]{Zhoukang Zhuang}%
\author[2]{Cheng Ma}%
\author[3]{Junying Ma}%
\author[3]{Jianhua Ju}%
\author[1]{Yanwen Duan}%
\author[1]{Xiangcheng Zhu}%
\affil[1]{Central South University}%
\affil[2]{National Engineering Research Center of Combinatorial Biosynthesis for Drug Discovery}%
\affil[3]{South China Sea Institute of Oceanology Chinese Academy of Sciences}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\selectlanguage{english}
\begin{abstract}
Tuberculosis (TB) and its emerged drug resistance exert huge threats on
the global health, therefore development of novel anti-TB antibiotics is
very essential. Ilamycin-E1/E2 is a pair of cycloheptapeptide
enantiomers obtained from a marine-derived Streptomyces atratus SCSIO
ZH16-\selectlanguage{greek}Δ\selectlanguage{english}ilaR mutant, and become promising anti-TB lead compounds due to
their significant anti-TB activities, but their low titer hampered the
further clinical development. In this work, the statistical
Plackett-Burman design (PBD) model was applied to screen out bacterial
peptone as the only significant but negative factor affecting the
ilamycin-E1/E2 production. Subsequent single factor optimization
revealed that replacement of bacterial peptone with malt extract
eliminated the accumulation of porphyrin-type competitive byproduct, and
the titer of ilamycin-E1/E2 in shaking flasks was improved from original
13.6\selectlanguage{ngerman}±0.8 to 142.7±5.7 mg/L for about 10.5 folds. Furthermore, a pH
coordinated feeding strategy was first adopted in scaled-up production
of ilamycin-E1/E2. The obtained titer of ilamycin-E1/E2 in 30L was
169.8±2.5 mg/L, while in 300L fermentor was only 131.5±7.5 mg/L due to
the unsynchronization of feeding response and pH change. Therefore, the
continuous pulse feeding strategy was further applied in 300L fermentor
and finally achieved 415.7±29.2 mg/L ilamycin-E1/E2, which represented
about 30.5 folds improvement at last. Our work provided the solid basis
to achieve sufficient ilamycin-E1/E2 lead compounds and support their
potential anti-TB drug development.%
\end{abstract}\selectlanguage{ngerman}%



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