Streptomycetes as platform for biotechnological production processes of drugs

Abstract

Streptomyces is one of the most versatile genera for biotechnological applications, widely employed as platform in the production of drugs. Although streptomycetes have a complex life cycle and metabolism that would need multidisciplinary approaches, review papers have generally reported only studies on single aspects like the isolation of new strains and metabolites, morphology investigations, and genetic or metabolic studies. Besides, even if streptomycetes are extensively used in industry, very few review papers have focused their attention on the technical aspects of biotechnological processes of drug production and bioconversion and on the key parameters that have to be set up. This mini-review extensively illustrates the most innovative developments and progresses in biotechnological production and bioconversion processes of antibiotics, immunosuppressant, anticancer, steroidal drugs, and anthelmintic agents by streptomycetes, focusing on the process development aspects, describing the different approaches and technologies used in order to improve the production yields. The influence of nutrients and oxygen on streptomycetes metabolism, new fed-batch fermentation strategies, innovative precursor supplementation approaches, and specific bioreactor design as well as biotechnological strategies coupled with metabolic engineering and genetic tools for strain improvement is described. The use of whole, free, and immobilized cells on unusual supports was also reported for bioconversion processes of drugs. The most outstanding thirty investigations published in the last 8 years are here reported while future trends and perspectives of biotechnological research in the field have been illustrated. KEY POINTS: • Updated Streptomyces biotechnological processes for drug production are reported. • Innovative approaches for Streptomyces-based biotransformation of drugs are reviewed. • News about fermentation and genome systems to enhance secondary metabolite production.

Keywords: Antibiotic; Bioconversion; Biotechnological process; Secondary metabolites; Steroid; Streptomyces.

Fig. 1

Different biotechnological applications of streptomycetes based on their life cycle. Streptomyces life cycle includes spore chains and spores that generally differentiate on solid media while the vegetative mycelium and aerial hyphae forms are obtained after growth in liquid cultures. According to the different life cycle phases and metabolism stages, the streptomycetes could be employed in diverse biotechnological applications

Fig. 2

SEM pictures of Streptomyces roseochromogenes ATCC 13400 in liquid cultures during hydrocortisone bioconversion at 0, 4, and 48 h, respectively (a–c): the accumulation of material on the cell surface is due to the process of steroid bioconversion and it is indicated by the arrows (c); SEM pictures of Streptomyces roseochromogenes ATCC 13400 whole cells as immobilized in calcium alginate beads (d–f): a tight mycelium was visible in the picture of bead internal view (f); SEM pictures of Streptomyces cyanogriseus ATCC 27426 in liquid cultures during secondary metabolite production at 96, 168, and 264 h, respectively (g–i): morphology changes with increase of cell tangling, branching, and rugosity are visible. (Mag from × 82 to × 20,000, scale bar from 2 to 200 μm). (Preparation of the samples for SEM analyses: small volumes of culture (1 mL) were pelleted end suspended in 4% formalin in PBS for 18 h, dehydrated in increasing ethanol concentrations (from 30 to 100% for 5–15 min), dried in a critical point dryer, and sputtered with platinum-palladium (sputter coater Denton Vacuum Desk V). Fe-SEM Supra 40 Zeiss (5 kV, detector InLens) and Smart SEM Zeiss software were used for observation