| Summary: | The clinical antibiotic gentamicin is a mixture of several difficult-to-separate components, the minor group of which is gentamicin C1a, a precursor for the synthesis of the high-efficacy and low-toxicity antibiotic etimicin. This study aimed to achieve the high production of gentamicin as well as gentamicin C1a. In this study, the influence of organic and inorganic salts on the gentamicin production was screened and label-free proteomics was used to determine the mechanisms responsible for the effects. In 25 L fermentation experiments, the addition of 0.1% CaCl<sub>2</sub> and 0.3% sodium citrate increased gentamicin titers by 11.5% (2398 μg/mL vs. 2150 μg/mL), while the C1a ratio increased from 38% to 42%. The results showed that CaCl<sub>2</sub> downregulated the synthesis and metabolism of the tetrapyrrole pathway and the GenK protein (0.08-fold) in the gentamicin synthesis pathway, whereas sodium citrate downregulated key proteins in the glycosylation pathway and tricarboxylic acid pathway. Thus, CaCl<sub>2</sub> caused changes in methylation during the synthesis of gentamicin, increasing the proportion of gentamicin C1a. In contrast, sodium citrate inhibited primary metabolism to promote the production of secondary metabolites of gentamicin. This study provided a basis for the co-production of gentamicin C1a mono-component and gentamicin multicomponent.
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