Otimização da produção de cromomicinas a partir de Streptomyces sp. BRA-384 isolada de Palythoa caribaeorum

Abstract

Cancer is a complex disease that affects thousands of Brazilians every year. This is the second leading cause of death in the world, with an estimated 625,000 new cases each year (2020-2022) in Brazil. Among the types of cancer, metastatic melanoma stands out for having a worse prognosis, and the mortality rate is high when discovered late. With this, the search for new chemotherapy, that have greater efficacy and lower side effects, is of paramount importance. Marine natural products (PNM) are a fruitful source of molecules with high pharmacological value, many of which are already used in the clinic for the treatment of various diseases, including cancer. Chromomycins are a class of molecules belonging to aurelic acids, with potent antitumor and antimicrobial activity produced and secreted by Streptomyces. To obtain different molecules with antitumor potential, the strain of Streptomyces sp. BRA-384 was cultured under different culture conditions (variations in time and two fermentation methods: in liquid or solid medium), and was subsequently submitted to the extraction of compounds, isolation of chromomycins and analysis of their antiproliferative activity. The method of fermentation and extraction in solid medium was considered the most efficient, because it presented a higher yield in the production of molecules, as well as for conferring a lower cost in the general process. From this fermentation it was possible to isolate 16 molecules by the HPLC method, and of these 11 were obtained with purity between 90-95%, 5 of which were already described in the literature (CA5-CA8). The isolated molecules had their antiproliferative activity evaluated by sulforodamine B (SRB) test, being tested in B16-F10 cells for 72 h. The results showed very potent activities even at concentrations in nM, obtaining IC50 (mean inhibiting concentration) of up to 42 ng/mL to P4, CA8 being the most potent among the chromomycins tested, presenting CI50 < 0.0001 nM. These findings reinforce the importance of proposing new cultivation methods that are capable of making biocomposite production faster and more efficient, besides providing the discovery of new molecules. The optmization method in solid plate suplys CA5 enough to carry out further in vivo studies due to its potency and yield as well.