loading page

Medium optimization and subsequent fermentative regulation for the scaled-up production of anti-tuberculosis drug leads ilamycin-E1/E2
  • +5
  • Zhiying Fan,
  • Nian Tong,
  • Zhoukang Zhuang,
  • Cheng Ma,
  • Junying Ma,
  • Jianhua Ju,
  • Yanwen Duan,
  • Xiangcheng Zhu
Zhiying Fan
Central South University

Corresponding Author:[email protected]

Author Profile
Nian Tong
Central South University
Author Profile
Zhoukang Zhuang
Central South University
Author Profile
Cheng Ma
National Engineering Research Center of Combinatorial Biosynthesis for Drug Discovery
Author Profile
Junying Ma
South China Sea Institute of Oceanology Chinese Academy of Sciences
Author Profile
Jianhua Ju
South China Sea Institute of Oceanology Chinese Academy of Sciences
Author Profile
Yanwen Duan
Central South University
Author Profile
Xiangcheng Zhu
Central South University
Author Profile

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-ΔilaR 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±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.
09 Aug 2021Submitted to Biotechnology Journal
10 Aug 2021Submission Checks Completed
10 Aug 2021Assigned to Editor
11 Aug 2021Reviewer(s) Assigned
06 Oct 2021Editorial Decision: Revise Minor
14 Oct 20211st Revision Received
15 Oct 2021Submission Checks Completed
15 Oct 2021Assigned to Editor
15 Oct 2021Reviewer(s) Assigned
07 Dec 2021Editorial Decision: Revise Minor
08 Dec 20212nd Revision Received
09 Dec 2021Submission Checks Completed
09 Dec 2021Assigned to Editor
09 Dec 2021Editorial Decision: Revise Minor
13 Dec 20213rd Revision Received
14 Dec 2021Submission Checks Completed
14 Dec 2021Assigned to Editor
14 Dec 2021Editorial Decision: Accept