The Daunomycin: Biosynthesis, Actions, and the Search for New Solutions to Enhance Production

Abstract

Daunorubicin (DNR) is an anthracycline antibiotic originating from soil-dwelling actinobacteria extensively used to treat malignant tumors. Over the decades, extensive attempts were made to enhance the production of anthracyclines by introducing genetic modifications and mutations in combination with media optimization, but the target production levels remain comparatively low. Developing an appropriate culture medium to maximize the yield of DNR and preventing autotoxicity for the producing organism remains a challenge. Our prospective review sheds light on a method involving perturbation that enhances the precursors to regulate the type II PKS pathway, enhancing cells' capacity to increase secondary metabolite production. The suggested method also entails the preparation of culture media for the cultivation of Streptomyces sp. and enhanced yield of DNR, as well as making it inactive with iron or its reduced forms following efflux from the producer. The iron or iron-DNR complex is encapsulated by oleic acid or lipid micelle layers in the culture media, finally resulting in the generated inactive DNR and the DNR-iron-oil complex. This idea has the potential to protect the producer organism from autotoxicity and prevent the inhibition of metabolite production. The approach of substituting sugar with oil in culture media has a dual role wherein it promotes Streptomyces growth by utilizing lipids as an energy source and encapsulating the generated DNR-iron complex in the medium. In this review, we discussed aspects like anthracycline producers, biosynthesis pathways, and gene regulation; side effects of DNR; mechanisms for autotoxicity evasion; and culture media components for the enhancement of DNR production in Streptomyces sp. We anticipate that our work will help researchers working with secondary metabolites production and decipher a methodology that would enhance DNR yield and facilitate the extraction of the resulting DNR by lowering costs in large-scale fermentation.

Keywords: Streptomyces; anthracyclines; autotoxicity; daunomycin; efflux; enhancement; oil-based medium.

Figure 1

Structure of daunorubicin (DNR) and doxorubicin (DOX) with the aglycone sugar moieties.

Figure 2

Biosynthesis pathway and involved genes of daunorubicin (DNR) and doxorubicin (DOX) in Streptomyces with (a) the aglycone moiety synthesis, (b) the sugar moiety, and (c) the glycosylation and post-modification steps in DNR/DOX synthesis.