| Summary: | The aminoglycoside antibiotic neomycin has broad antibacterial properties and is widely used in medicine and agriculture. With the discovery of neomycin’s potential applications in treating tumors and SARS-CoV-2, it is necessary to accelerate the biosynthesis of neomycin. In the present study, we investigated the effects of various inorganic salts on neomycin B (the main active neomycin) biosynthesis in <i>Streptomyces fradiae</i> SF-2. We found that 60 mM (NH<sub>4</sub>)<sub>2</sub>SO<sub>4</sub> could promote neomycin B biosynthesis and cell growth most effectively. Further comparative transcriptomic analyses revealed that 60 mM (NH<sub>4</sub>)<sub>2</sub>SO<sub>4</sub> inhibited the EMP and TCA cycles and enhanced the expression of <i>neo</i> genes involved in the neomycin B biosynthesis pathway. Finally, a neomycin B potency of 17,399 U/mL in shaking flasks was achieved by overexpressing <i>neoE</i> and adding 60 mM (NH<sub>4</sub>)<sub>2</sub>SO<sub>4</sub>, corresponding to a 51.2% increase compared with the control <i>S. fradiae</i> SF-2. In the present study, the mechanism by which (NH<sub>4</sub>)<sub>2</sub>SO<sub>4</sub> affects neomycin biosynthesis was revealed through transcriptomics, providing a reference for the further metabolic engineering of <i>S. fradiae</i> SF-2 for neomycin B production.
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