Abstract
Saccharomonospora sp. UR22 and Dietzia sp. UR66, two actinomycetes derived from the Red Sea sponge Callyspongia siphonella, were co-cultured and the induced metabolites were monitored by HPLC-DAD and TLC. Saccharomonosporine A (1), a novel brominated oxo-indole alkaloid, convolutamydine F (2) along with other three known induced metabolites (3-5) were isolated from the EtOAc extract of Saccharomonospora sp. UR22 and Dietzia sp. UR66 co-culture. Additionally, axenic culture of Saccharomonospora sp. UR22 led to isolation of six known microbial metabolites (6-11). A kinase inhibition assay results showed that compounds 1 and 3 were potent Pim-1 kinase inhibitors with an IC50 value of 0.3 ± 0.02 and 0.95 ± 0.01 μM, respectively. Docking studies revealed the binding mode of compounds 1 and 3 in the ATP pocket of Pim-1 kinase. Testing of compounds 1 and 3 displayed significant antiproliferative activity against the human colon adenocarcinoma HT-29, (IC50 3.6 and 3.7 μM, respectively) and the human promyelocytic leukemia HL-60, (IC50 2.8 and 4.2 μM, respectively). These results suggested that compounds 1 and 3 act as potential Pim-1 kinase inhibitors that mediate the tumor cell growth inhibitory effect. This study highlighted the co-cultivation approach as an effective strategy to increase the chemical diversity of the secondary metabolites hidden in the genomes of the marine actinomycetes.
Highlights
Marine sponge-associated microorganisms have been proved an essential source of biologically active natural products (Thomas et al, 2010; Roue et al, 2012; Abdelmohsen et al, 2014a)
Examples of the production of induced new natural products by co-fermentation of marine derived microorganisms include a rare class of pseurotins, 11-O-methylpseurotin A2 derived from mixed fermentation of Streptomyces bullii and the fungus Aspergillus fumigatus MBC-F1-10 (Rateb et al, 2013), the cyclic depsipeptides emericellamides A and B isolated from a co-culture of marine-derived fungus Emericella sp. (CNL-878) and the marine bacterium Salinispora arenicola (Oh et al, 2007), the diterpenoids libertellenones A–D isolated from mixed fermentation of the marine α-proteobacterium strain CNJ-328 with the fungus and Libertella sp
Guided by High performance liquid chromatography (HPLC)-DAD, the EtOAc extracts from the liquid cultures of the axenic fermentations and mixed fermentation were subjected to Sephadex LH-20 column chromatography followed by C18 reversed-phase column chromatography and final preparative TLC purification to target the isolation of the new metabolites 1 and 2 together with the other nine known metabolites 3-11
Summary
Marine sponge-associated microorganisms have been proved an essential source of biologically active natural products (Thomas et al, 2010; Roue et al, 2012; Abdelmohsen et al, 2014a). Due to the continuous discovery of bioactive natural products from marine microbes, re-isolation of known microbial secondary metabolites has become a real challenge (Hong et al, 2009). Co-cultivation of two different microbial strains together in one culture allows direct interaction between them, which may lead to the induction of new cryptic secondary metabolites not previously detected in the axenic cultures (Rateb et al, 2013). We report on the induction of new bioactive secondary metabolites (Figure 1) saccharomonosporine A (1) and convolutamydine F (2) along with other three known metabolites 3-5 in response to microbial co-cultivation of two marine actinomycetes, Saccharomonospora sp.
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