Bioprocess optimization for nocuolin A production in Nodularia sp. LEGE 06071

Cyanobacteria have emerged as promising producers of metabolites with biotechnological relevance including microcystins, nostocyclopeptides, and cryptophycins, which exhibit antitumor, antimicrobial, and enzyme-inhibitory activities. These compounds are usually produced in small amounts, representing a major limitation to their potential commercialization. Improving upstream and downstream bioprocessing of these metabolites may be key to making cyanobacterial secondary metabolites economically competitive. Here, an efficient method for nocuolin A extraction is presented, partially validated in accordance with the European Legislation. Moreover, Nodularia sp. LEGE 06071 was subjected to a series of bioprocess optimization screenings focused on light conditions (quality, photoperiods and intensity). This resulted in the selection of optimal light conditions for the target metabolite productivity (white light, 100 μmol m⁻² s⁻¹, 16 h/8 h (light/dark)) and in a fivefold improvement when compared to standard cultivation conditions. Finally, nutrient availability was accessed using a Plackett-Burman design, allowing for the selection of the main nutrients affecting nocuolin A accumulation (nitrate and phosphate), followed by testing of different N:P ratios, leading to the identification of a ratio of 1 for enhanced metabolite productivity, resulting in a further improvement in the final productivity of 57 % (overall improvement of 557 %).