Abstract
Deepsea microbes are a rich source of novel bioactive compounds, which have developed unique genetic systems as well as biosynthetic pathways compared with those of terrestrial microbes in order to survive in extreme living environment. However, a large variety of deepsea-microbial secondary metabolic pathways remain “cryptic” under the normal laboratory conditions. Manipulation of global regulators is one of the effective approaches for triggering the production of cryptic secondary metabolites. In this study, by combination of various chromatographic purification process, we obtained somalimycin (1), a new antimycin-type depsipeptide, with an unusual substitution of 3-aminosalicylate instead of conserved 3-formamidosalicylate moiety, along with two known (2 and 3) analogs from the ΔwblAso mutant strain of deepsea-derived Streptomyces somaliensis SCSIO ZH66. The structures of 1–3 were elucidated on the basis of extensive spectroscopic analyses including LC-MS and NMR. In the evaluation of potent anti-inflammatory activity, compound 2 exhibited strong inhibitory activity on the IL-5 production in ovalbumin-stimulated splenocytes with IC50 value of 0.57 μM, while 1 and 3 displayed mild effect (>10 μM), which might be attributed to their different side-chain substitutions. Moreover, compounds 1–3 showed very weak cytotoxicity against human umbilical vein endothelial cells with LD50 values of 62.6, 34.6, and 192.9 μM, respectively, which were far over their IL-5 inhibitory activity. These results indicated that these compounds have good potential for further use in anti-inflammatory drug development.
Highlights
Marine natural products are a rich source of drug candidates, an increasing number of which have been approved to the market or are currently in clinical trials (Newman and Cragg, 2004; Salomon et al, 2004; Kollar et al, 2014; Rangel and Falkenberg, 2015)
The wblAso mutant strain of S. somaliensis SCSIO ZH66 was obtained as described in our previous study (Huang et al, 2016)
Antimycin-type compounds are a class of depsipeptides sharing a nine-membered bis-lactone ring with a conserved substitution of 3-formamidosalicylic acid, which exhibited a wide range of bioactivities including antifungal, insecticidal, antiviral, anticancer, and anti-inflammatory (Hosotani et al, 2005; Shiomi et al, 2005; Raveh et al, 2013; Liu J. et al, 2016)
Summary
Marine natural products are a rich source of drug candidates, an increasing number of which have been approved to the market or are currently in clinical trials (Newman and Cragg, 2004; Salomon et al, 2004; Kollar et al, 2014; Rangel and Falkenberg, 2015). In the expanding search for sources of new chemical and bioactivity diversity, the exploration of deepsea microbes has emerged as a new frontier in drug discovery and development. In the long process of evolution, deepsea microbes developed unique genetic systems as well as different biosynthetic pathways compared with those of terrestrial microbes for good adaption to extreme living environment, which enables them to produce a large diversity of structurally novel and biologically active secondary metabolites (Skropeta, 2008; Skropeta and Wei, 2014). With the recent advances in genomics and bioinformatics analytical techniques, genome-guided compound mining, the key point of which is to find ways to turn on or turn up the expression of cryptic or poorly expressed pathways to trigger novel compound production, has been used as a more efficient approach compared to those traditional methods for novel bioactive compound discovery (Challis, 2008; Lane and Moore, 2011; Bachmann et al, 2014)
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