Journal Articles - UP - MSI
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- A conserved biosynthetic gene cluster is regulated by quorum sensing in a shipworm symbiontRobes, Jose Miguel D.; Altamia, Marvin A.; Murdock, Ethan G.; Concepcion, Gisela; Haygood, Margo G.; Puri, Aaron W. (American Society for Microbiology, 2022-06-14)Bacterial symbionts often provide critical functions for their hosts. For example, wood-boring bivalves called shipworms rely on cellulolytic endosymbionts for wood digestion. However, how the relationship between shipworms and their bacterial symbionts is formed and maintained remains unknown. Quorum sensing (QS) often plays an important role in regulating symbiotic relationships. We identified and characterized a QS system found in Teredinibacter sp. strain 2052S, a gill isolate of the wood-boring shipworm Bactronophorus cf. thoracites. We determined that 2052S produces the signal N-decanoyl-l-homoserine lactone (C10-HSL) and that this signal controls the activation of a biosynthetic gene cluster colocated in the symbiont genome that is conserved among all symbiotic Teredinibacter isolates. We subsequently identified extracellular metabolites associated with the QS regulon, including ones linked to the conserved biosynthetic gene cluster, using mass spectrometry-based molecular networking. Our results demonstrate that QS plays an important role in regulating secondary metabolism in this shipworm symbiont. This information provides a step toward deciphering the molecular details of the relationship between these symbionts and their hosts. Furthermore, because shipworm symbionts harbor vast yet underexplored biosynthetic potential, understanding how their secondary metabolism is regulated may aid future drug discovery efforts using these organisms.
- Somatostatin venom analogs evolved by fish-hunting cone snails: From prey capture behavior to identifying drug leadsRamiro, Iris Bea L.; Bjørn-Yoshimoto, Walden E.; Imperial, Julita S.; Gajewiak, Joanna; Salcedo, Paula Flórez; Watkins, Maren; Taylor, Dylan; Resager, William; Ueberheide, Beatrix; Bräuner-Osborne, Hans; Whitby, Frank G.; Hill, Christopher P.; Martin, Laurent F.; Patwardhan, Amol; Concepcion, Gisela; Olivera, Baldomero M.; Safavi-Hemami, Helena (American Association for the Advancement of Science, 2022-03-25)Somatostatin (SS) is a peptide hormone with diverse physiological roles. By investigating a deep-water clade of fish-hunting cone snails, we show that predator-prey evolution has generated a diverse set of SS analogs, each optimized to elicit specific systemic physiological effects in prey. The increased metabolic stability, distinct SS receptor activation profiles, and chemical diversity of the venom analogs make them suitable leads for therapeutic application, including pain, cancer, and endocrine disorders. Our findings not only establish the existence of SS-like peptides in animal venoms but also serve as a model for the synergy gained from combining molecular phylogenetics and behavioral observations to optimize the discovery of natural products with biomedical potential.
- Mining small molecules from Teredinibacter turnerae strains isolated from Philippine TeredinidaeVillacorta, Jamaine B.; Rodriguez, Camille V.; Peran, Jacquelyn E.; Batucan, Jeremiah D.; Concepcion, Gisela; Salvador-Reyes, Lilibeth A.; Junio, Hiyas A. (MDPI, 2022-11-21)Endosymbiotic relationship has played a significant role in the evolution of marine species, allowing for the development of biochemical machinery for the synthesis of diverse metabolites. In this work, we explore the chemical space of exogenous compounds from shipworm endosymbionts using LC-MS-based metabolomics. Priority T. turnerae strains (1022X.S.1B.7A, 991H.S.0A.06B, 1675L.S.0A.01) that displayed antimicrobial activity, isolated from shipworms collected from several sites in the Philippines were cultured, and fractionated extracts were subjected for profiling using ultrahigh-performance liquid chromatography with high-resolution mass spectrometry quadrupole time-of-flight mass analyzer (UHPLC-HRMS QTOF). T. turnerae T7901 was used as a reference microorganism for dereplication analysis. Tandem MS data were analyzed through the Global Natural Products Social (GNPS) molecular networking, which resulted to 93 clusters with more than two nodes, leading to four putatively annotated clusters: lipids, lysophosphatidylethanolamines, cyclic dipeptides, and rhamnolipids. Additional clusters were also annotated through molecular networking with cross-reference to previous publications. Tartrolon D cluster with analogues, turnercyclamycins A and B; teredinibactin A, dechloroteredinibactin, and two other possible teredinibactin analogues; and oxylipin (E)-11-oxooctadec-12-enoic acid were putatively identified as described. Molecular networking also revealed two additional metabolite clusters, annotated as lyso-ornithine lipids and polyethers. Manual fragmentation analysis corroborated the putative identification generated from GNPS. However, some of the clusters remained unclassified due to the limited structural information on marine natural products in the public database. The result of this study, nonetheless, showed the diversity in the chemical space occupied by shipworm endosymbionts. This study also affirms the use of bioinformatics, molecular networking, and fragmentation mechanisms analysis as tools for the dereplication of high-throughput data to aid the prioritization of strains for further analysis.The research was completed under the supervision of the Department of Agriculture-Bureau of Fisheries and Aquatic Resources (DA-BFAR), Philippines in compliance with Prior Informed Consent (PIC) certificate requirements and all required legal instruments and regulatory issuances covering the conduct of the research. The authors would also like to acknowledge the Department of Science and Technology-funded Discovery and Development of Health Products Program (DOST-DDHP) for the LC-MS Facility of the Institute of Chemistry, University of the Philippines Diliman.
- Local tide and geoid corrections significantly improve coastal retracked Jason sea surface heights in the PhilippinesFlores, Paul Caesar; Reyes, Rosalie; Amedo-Repollo, Charina Lyn; Rediang, Abegail; Alfante, Rey Mark; Bauzon, Ma. Divina Angela; Pasaje, Nikki; Bringas, Dennis (Science and Technology Information Institute, 2022-11-08)Retracking algorithms increase the accuracy of coastal sea surface height (SSH) measurements. However, it is still important to validate these retracking estimates with tide gauge (SSHtg) observations. We downloaded the freely available Jason altimeter SSH processed using the XTRACK-ALES algorithm, then detided the SSH using different tide models. The first model is the default tidal correction based on Finite Element Solution 2014 (SSHfes), and the second model is the T_Tide harmonic analysis of the nearest tide gauge (SSHaltimeter). SSHfes showed a very poor correlation (< 0.31) and very high root mean square error (RMSE, > 29 cm). In contrast, SSHaltimeter generally showed a very high correlation (> 0.91) and low RMSE (< 17.4 cm). A further quality check based on the average and standard deviation of the difference between the SSH readings (SSHfes – SSHtg and SSHaltimeter – SSHtg) also showed the superior performance of SSHaltimeter,which scored < 9.3 and < 16.5 cm, respectively; compared to SSHfes, which scored < 9.3 cm and > 27 cm for the same parameters. The poor performance from the SSHfes likely comes from the complex bathymetry and coastal geomorphology of the country, which is not accounted for in the FES. The Philippines generally has a narrow shelf, and the FES tide corrections may be related to deep-water tides rather than the shallow-water tides observed from tide gauges. Despite the high correlation and agreement between the SSHaltimeter and SSHtg, the rate of sea level rise from the SSHaltimeter in some sites is more than twice the rate from SSHtg, which indicates the possible influence of the vertical land movement.This study was supported by grants to R.B. Reyes by the Department of Science and Technology–Philippine Council for Industry, Energy, and Emerging Technology Research and Development through the Coastal Sea Level Rise Philippines Project. We also thank the anonymous reviewers for their feedback on how to improve the manuscript.
- Synthesis and biological evaluation of cyanobacterial-inspired peptidesCasanova, Jannelle R.; Villaraza, Aaron Joseph L.; Salvador-Reyes, Lilibeth (Philippine-American Academy of Science and Engineering, 2024-03-18)Cyanobacteria are known producers of structurally diverse and potent natural products; the majority are peptides with unique modifications. Yet, there remains a huge underexplored chemodiversity from cyanobacteria. Here, we designed a linear octapeptide as a product of combinatorial peptide design inspired by the natural products from the filamentous cyanobacteria Hapalosiphon welwitschii and Leptolyngbya sp. The target peptide was synthesized via solid-phase peptide synthesis (SPPS) using fluorenylmethyloxycarbonyl-protecting group (Fmoc) strategy. Structural diversity was expanded by the substitution of unnatural amino acids to yield five analogues. The structure and sequence of the synthesized peptides were confirmed using nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). Biological activity evaluation was done; with none of the peptides showing antimicrobial or cytotoxic activities against microbial pathogens and mammalian cells, respectively. To our knowledge, this study is the first to report a combinatorial peptide design inspired by a natural product and a predicted biosynthetic product. This strategy of peptide design expands the chemistry of a known bioactive natural product with the aid of unexplored cyanobacterial biosynthetic gene clusters.This study was funded by the Philippine Council for Health Research and Development – Department of Science and Technology through the Discovery and Development of Health Products – Marine Component Program. J.R.C acknowledges scholarship support from the Accelerated Science and Technology Human Resource Development Program of the Department of Science and Technology – Science Education Institute. We acknowledge the assistance of Z. Malto, J. Peran and S. Susana in the conduct of the biological assays. This is MSI Contribution No. 502.
- 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.