The enhancement of rapamycin production using Streptomyces hygroscopicus through a simple pH-shifted control

Rapamycin, a ring macrolide compound, is recognized as a potent immunosuppressive drug which works by inhibiting T-cell activation and proliferation and is also characterized as having cancer-fighting and anti-aging functions. The pellet morphology of Streptomyces hygroscopius was suggested to have the high rapamycin production titer. The change of culturing pH could alter the morphology of actinomycetes. Therefore, the influence of pH level on rapamycin production was examined. No significant effects of initial pH on rapamycin production were observed in the pH range of 6–8 in the flask trials. Nevertheless, a two-stage pH control strategy was proposed in a bench-scale fermenter, with no pH control in the 1st stage and with the pH controlled at 5.5 in the 2nd stage after the pH rebounded from the bottom. A recorded high rapamycin level of 537 ± 23 mg/L was obtained in a simple batch operation, far higher than the 45 ± 5 and 98 ± 5 mg/L levels in the batches with the pH maintained at a fixed level of 7.0 and without the pH controlled, respectively. The strategy of a two-stage pH control was simple to operate and potentially applied in the scaled-up production of rapamycin.

► The change of culturing pH could alter the morphology of actinomyces. ► No significant effects of initial pH on rapamycin production were observed. ► A successful two-stage pH controlled strategy that could obviously enhance rapamycin production.