Combinatorial strategies for production improvement of anti-tuberculosis antibiotics ilamycins E/E from deep sea-derived Streptomyces atratus SCSIO ZH16 ΔilaR.

Ilamycins E/E are novel cyclic heptapeptides from Streptomyces atratus SCSIO ZH16, which have the MIC value of 9.8 nM against Mycobacterium tuberculosis H37Rv. However, the lower fermentative titer of ilamycins E/E cut off further development for novel anti-TB lead drugs. In order to break the obstacle, the combinatorial strategy of medium optimization, fermentative parameters optimization, exogenous addition of metal ions, precursors, and surfactants was developed to promoted the production of ilamycins E/E. Addition of 1 mM ZnCl at 0 h, 1 g/L tyrosine at 96 h, and 2 g/L shikimic acid at 48 h increased the production of ilamycins E/E from 13.51 to 762.50 ± 23.15, 721.39 ± 19.13, and 693.83 ± 16.86 mg/L, respectively. qRT-PCR results showed that the transcription levels of key genes in Embden-Meyerhof-Parnas pathway, hexose phosphate shunt pathway, and shikimic acid pathway were upregulated. In addition, the production of ilamycins E/E reached 790.34 mg/L in a 5-L bioreactor by combinatorial strategy. Combinatorial strategies were used for improving ilamycins E/E production in S. atratus ΔilaR and provided a sufficient basis on further clinic development.