National Committee on Marine Sciences (NCMS)
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- Anti-inflammatory activity of monosubstituted xestoquinone analogues from the marine sponge Neopetrosia compactaSusana, Shalice R.; Salvador-Reyes, Lilibeth A. (MDPI, 2022-03-22)Chronic inflammation is recognized as a contributor to multiple chronic diseases, such as cancer, cardiovascular, and autoimmune disorders. Here, a natural products-initiated discovery of anti-inflammatory agents from marine sponges was undertaken. From the screening of 231 crude extracts, a total of 30 extracts showed anti-inflammatory activity with no direct cytotoxic effects at 50 μg/mL on RAW 264.7 (ATCC®TIB-71™) murine macrophage cells stimulated with 1 μg/mL lipopolysaccharide (LPS). Bioactivity-guided purification of the anti-inflammatory extract from the sponge Neopetrosia compacta led to the isolation of xestoquinone (1), adociaquinone B (2), adociaquinone A (3), 14-hydroxymethylxestoquinone (4), 15-hydroxymethylxestoquinone (5), and an inseparable 2:1 mixture of 14-methoxyxestoquinone and 15-methoxyxestoquinone (6). Compounds 1–6 caused a concentration-dependent reduction of nitric oxide (NO) production in LPS-stimulated RAW 264.7 cells, with 4–6 having low micromolar IC50 and acceptable selectivity index. Gene expression analysis using qRT-PCR showed that 1, 5, and 6 downregulated Il1b and Nos2 expression by 2.1- to 14.8-fold relative to the solvent control at 10 μM. Xestoquinone (1) and monosubstituted analogues (4–6), but not the disubstituted adociaquinones (2 and 3), caused Nrf2 activation in a luciferase reporter MCF7 stable cells. Compounds 5 and 6 caused a modest increase in Nqo1 gene expression at 10 μM. The anti-inflammatory activity of xestoquinone (1) and monosubstituted analogues (4–6) may, in part, be mediated by Nrf2 activation, leading to attenuation of inflammatory mediators such as IL-1β and NOS2.Samples were collected under gratuitous permit numbers GP-0084-15 and GP-0123-17, issued by the Department of Agriculture of the Philippines. We thank the municipalities of Bolinao, Pangasinan, and Puerto Galera, Oriental Mindoro for permission for sample collection. We acknowledge assistance from Z. L. Malto and DDHP chemical ecology group in obtaining the mass spectrometric data and sample collection, respectively.
- Genomics and metabolomics-based assessment of the biosynthetic potential of the sponge-associated microorganism Streptomyces cacaoi strain R2A-843A from the PhilippinesMalto, Zabrina Bernice L.; Reyes, Joeriggo M.; Lo, Bernard Isaiah; Davis, Kevin Bossie S.; Concepcion, Gisela; Salvador-Reyes, Lilibeth A. (Philippine-American Academy of Science and Engineering, 2023-10-20)The biosynthetic machinery of the sponge-associated Streptomyces cacaoi strain R2A-843A was assessed using a combined genomics and metabolomics approach. Whole genome sequencing and molecular networking showed the high biosynthetic potential of this actinomycete. A significant proportion of the genome is dedicated to secondary metabolite production, with biosynthetic gene clusters for nonribosomal peptides, polyketides, and terpenes being the most represented. Seven cyclic pentapeptides, including a putative new analogue, and a glycosylated lanthipeptide were identified using HRMS and untargeted MS/MS analysis. To validate our genome and metabolome analysis, we undertook a mass spectrometry-guided purification and confirmed the production of the known peptides BE-18257A (1) and BE-18257B (2). The production of 1 and 2 and the growth of the microorganism were monitored for eight days. Compound 2 was produced at a higher concentration, starting at 48 h post-incubation. Both compounds were noncytotoxic against colorectal and breast cancer cell lines.The authors acknowledge funding support from the Department of Science and Technology - Philippine Council for Health Research and Development through the Discovery and Development of Health Products - Marine Component Program. Genome sequencing was made possible through the CHEDPCARI IHITM63 Project. We thank Ms. Shalice R. SusanaGuevarra for conducting the bioactivity assay. This work was done under the supervision of the Bureau of Fisheries and Aquatic Resources under Gratuitous Permit No. FBP-0035-10. This is MSI Contribution No. 501.
- Genome mining of a novel marine sponge symbiont Nocardia sp. BML-15-R-026U reveals high biosynthetic potential for secondary metabolites, including a non-ribosomal peptide and a polyketide of high noveltyGloria, Paul Christian; Romines, Elaine; Punzalan, Marc Jeremie; Florece, Christine Marie; Cadorna, Kreighton; Salvador-Reyes, Lilibeth; Lluisma, Arturo (Philippine-American Academy of Science and Engineering, 2023-11-28)Antibiotic and drug resistance poses serious global public health threats, leading to substantial infections and fatalities annually. Addressing these issues requires the discovery of novel bioactive compounds and a faster and more cost-effective discovery process. However, traditional approaches, which require isolation and multi-step purification of compounds from organisms and running of initial assays, suffer from serious limitations such as the need for substantial amounts of biological material and high rates of compound rediscoveries. Because the biosynthetic capabilities of organisms are encoded in their genomes, genome mining provides a promising solution that would complement traditional approaches. This study conducted long-read whole genome sequencing on a marine sponge symbiont, Nocardia sp. BML-15-R-026U, to explore its genomic repertoire of secondary metabolite-encoding Biosynthetic Gene Clusters (BGCs). A four-contig genome assembly was generated for this isolate with a high degree of completeness and an estimated genome size of 4.84 Mbp. Its genome displays remarkable biosynthetic potential by containing at least 34 distinct secondary metabolite BGCs, predominantly Non-Ribosomal Peptide Synthetase (NRPS) and Polyketide Synthase (PKS) systems capable of producing novel chemical structures. Further analysis was focused on two genomic regions. In region 3.10, the study predicted a BGC for a novel, serine-rich non-ribosomal peptide with a predicted molecular weight of 2754 g/mol. Region 3.12 contained an iterative type-I PKS BGC, suggesting the potential synthesis of a polyketide compound with oxidoreductase-inhibiting properties. This study highlights genome mining as a productive early-phase approach for identifying promising drug leads and has identified the most promising candidates among this isolate’s BGCs for experimental validation.The study was funded by the Philippine Council for Health Research and Development – Department of Science and Technology under the “Anti-infective and Anticancer Drug Candidates from Marine Microorganisms and Sponges: Discovery and Development” project, Marine Science Institute – UP Diliman. The authors would like to thank the researchers of the Marine Genomics and Molecular Genetics Laboratory, MSI. The authors would also like to thank the researchers of the Discovery and Development of Health Products – Marine Component Phase I and researchers of the Marine Pharmacognosy Laboratory for the collection and initial analysis of the sample used in this study and storage and maintenance of the bacterial cultures. Sample collection was done under Gratuitous Permit No. GP-0084-15.