Pudhuvai Baveesh, Beneš Karel, Čurn Vladislav, Bohata Andrea, Lencova Jana, Vrzalova Radka, Barta Jan, Matha Vladimir
Department of Genetics and Biotechnology, Faculty of Agriculture and Technology, University of South Bohemia in České Budějovice, Studentská 1668, 370 05 České Budějovice, Czech Republic.
VUAB Pharma A.S, Nemanicka 2722, 370 01 České Budějovice, Czech Republic.
Microorganisms. 2024 Dec 19;12(12):2639. doi: 10.3390/microorganisms12122639.
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 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 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 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.
柔红霉素（DNR）是一种源自土壤放线菌的蒽环类抗生素，广泛用于治疗恶性肿瘤。几十年来，人们通过引入基因修饰和突变并结合培养基优化等方式，进行了大量提高蒽环类药物产量的尝试，但目标产量水平仍然相对较低。开发一种合适的培养基以最大化DNR产量并防止产生菌发生自毒作用仍然是一项挑战。我们的前瞻性综述揭示了一种涉及扰动的方法，该方法可增强前体以调节II型聚酮合酶途径，从而提高细胞产生次生代谢产物的能力。所建议的方法还包括制备用于培养 sp.的培养基，提高DNR产量，并使其在从产生菌中流出后与铁或其还原形式失活。铁或铁-DNR复合物在培养基中被油酸或脂质微胶粒层包裹，最终产生失活的DNR和DNR-铁-油复合物。这一想法有可能保护产生菌免受自毒作用，并防止代谢产物产生受到抑制。在培养基中用油替代糖的方法具有双重作用，即通过利用脂质作为能源促进生长，并将产生的DNR-铁复合物包裹在培养基中。在本综述中，我们讨论了蒽环类产生菌、生物合成途径和基因调控等方面；DNR的副作用；逃避自毒作用的机制；以及用于提高 sp.中DNR产量的培养基成分。我们预计，我们的工作将有助于从事次生代谢产物生产的研究人员，并解读一种能够提高DNR产量并通过降低大规模发酵成本来促进所得DNR提取的方法。
