Edited by: Jem Stach, Newcastle University, United Kingdom
Reviewed by: Polpass Arul Jose, Central Salt and Marine Chemicals Research Institute (CSIR), India; Vijay Kumar, Doon (P.G) College of Agriculture Science and Technology, India; D. Ipek Kurtboke, University of the Sunshine Coast, Australia
*Correspondence: Jae Kyung Sohng
This article was submitted to Antimicrobials, Resistance and Chemotherapy, a section of the journal Frontiers in Microbiology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Actinobacteria are prolific producers of thousands of biologically active natural compounds with diverse activities. More than half of these bioactive compounds have been isolated from members belonging to actinobacteria. Recently, rare actinobacteria existing at different environmental settings such as high altitudes, volcanic areas, and marine environment have attracted attention. It has been speculated that physiological or biochemical pressures under such harsh environmental conditions can lead to the production of diversified natural compounds. Hence, marine environment has been focused for the discovery of novel natural products with biological potency. Many novel and promising bioactive compounds with versatile medicinal, industrial, or agricultural uses have been isolated and characterized. The natural compounds cannot be directly used as drug or other purposes, so they are structurally modified and diversified to ameliorate their biological or chemical properties. Versatile synthetic biological tools, metabolic engineering techniques, and chemical synthesis platform can be used to assist such structural modification. This review summarizes the latest studies on marine rare actinobacteria and their natural products with focus on recent approaches for structural and functional diversification of such microbial chemicals for attaining better applications.
Actinobacteria are Gram-positive bacteria with high GC contents in DNA. They have characteristics presence of intracellular proteasomes, and spores if present are exospores (Cavalier-Smith,
The un-explored and under-explored habitats including marine ecosystems are believed to be rich sources of such rare actinobacteria, with tremendous potential to produce interestingly new compounds (Hong et al.,
Generally, for uncovering the marine rare actinobacteria, isolation efforts have been focused on rare locations as deep-sea sediments to obtain new marine diversities (Fenical and Jensen,
Moreover, the laborious microscopic techniques are being replaced with techniques utilizing recent advances in genomics, proteomics, and bioinformatics for identification and characterization of microbial diversity in robust manner (Rastogi and Sani,
Overview of achievements in study of bioactive molecules derived from marine rare actinobacteria.
Pseudonocardians | Deep-sea sediment of South China Sea | Pseudonocardia sp. SCSIO 01299 | Antibacterial and cytotoxic | Li et al., |
Caerulomycins | Marine sediments from the seashore of Weihai, China | Cytotoxic, antibacterial | Fu et al., |
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Marinacarbolines, | Marine sediment sample from South China Sea | Antimalarial | Huang et al., |
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Salinosporamides (Commercial name |
Deep sea-water of Bahamas Islands, Bahamas | Cytotoxic | Feling et al., |
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Abyssomicins | Sediment sample from the Sea of Japan, Japan | Antibacterial | Bister et al., |
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Marinomycins | Sediment sample offshore of La Jolla, USA | Cytotoxic | Kwon et al., |
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Levantilides | Deep-sea sediment Eastern Mediterranean Sea | Cytotoxic | Gärtner et al., |
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Salinoquinones | Deep sea-water of Bahamas Islands, Bahamas | Cytotoxic | Murphy et al., |
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Neomaclafungin | Marine sediment from Usa bay, Kochi Prefecture, Japan. | Antifungal | Sato et al., |
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Marthiapeptide A | Deep-sea sediment of the South China Sea | Antibacterial, Cytotoxic | Zhou et al., |
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Lucentamycins | Sediment sample from Bahamas island, Bahamas | Cytotoxic | Cho et al., |
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Juvenimicin C | Sediment collected off the coast of Palau, USA | Cancer chemo preventive | Carlson et al., |
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Levantilide C | Shallow coastal waters near the island of Chiloe, Chile. | Antiproliferative | Fei et al., |
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Nocapyrones | Sediment sample, Ulleung Basin, Eastern sea, Korea | Reduced the pro-inflammatory factor | Kim et al., |
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Nocardiamides | Sediment sample from La Jolla Canyon, San Diego, California, USA. | Low antibacterial activity | Wu Z. C. et al., |
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Cyanogramides | Marine sediments from the seashore of Weihai, China | Multidrug-resistance (MDR) reversing activity | Fu et al., |
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Taromycin | Marine sediment sample from La Jolla Submarine Canyon, San Diego, California, USA. | Antibacterial | Yamanaka et al., |
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Lodopyridone | Marine sediment sample from La Jolla Submarine Canyon, San Diego, California, USA. | Modest cytotoxic activity | Maloney et al., |
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Lynamicins | Marine sediment off the coast of San Diego, California, USA | Antibacterial | McArthur et al., |
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Saccharothrixones | Sediment sample from Heishijiao Bay, Dalian, China | Cytotoxic | Gan et al., |
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Saliniketals | Sediment sample from Island of Guam, USA | Prevention of carcinogenesis | Williams et al., |
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Arenicolides | Sediment sample from Island of Guam, USA | Moderate cytotoxicity | Williams et al., |
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Lagumycin B, Dehydrorabelomycin, Phenanthroviridone, WS-5995 A | Sediment sample from Cát Bà Peninsula, East Sea Vietnam | Cytotoxic | Mullowney et al., |
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Dermacozines, Phenazine derivatives | Sediment sample from Mariana Trench | Cytotoxic and anti-oxidant | Abdel-Mageed et al., |
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Fijiolides | Sediment sample from the Beqa Lagoon, Fiji | Inhibitor of TNF-α-induced NFκB activation | Nam et al., |
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Fluostatin | Sediment sample from South China Sea | Antimicrobial | Zhang et al., |
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Retimycin | Deep sea-water of Bahamas Islands, Bahamas | Cytotoxic | Duncan et al., |
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Sioxanthin | Deep sea-water of Bahamas Islands, Bahamas | Siderophore | Richter et al., |
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Lobosamides | Sediment sample from Point Lobos, Monterey Bay, California, USA. | Antitryposomal | Schulze et al., |
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Salinipostins | Sediment sample from Keawekaheka Bay, Hawai, USA | Antimalarial | Schulze et al., |
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Isomethoxyneihumicin | Sediment sample at Chichijima, Ogasawara, Japan | Cytotoxic | Fukuda et al., |
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Nocarimidazoles | Sediment sample off the coast of southern California, USA | Weak antibacterila | Leutou et al., |
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Cyclomarine Cyclomarazine | Marine sediment from Palau, Republic of Palau | Anti-inflammatory | Schultz et al., |
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JBIR-65 | Symbiont to unidentified marine sponge from Ishigaki Island, Okinawa Prefecture, Japan | Anti-oxidant | Takagi et al., |
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Nocapyrones | Symbiont to sponge |
Weak cytotoxic | Schneemann et al., |
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Arenjimycin | Symbiont to ascidian |
Antimicrobial and ytotoxic | Asolkar et al., |
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Bendigoles | Symbiont to sponge |
Antimicrobial and cytotoxic | Simmons et al., |
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Thiocoraline | Symbiont to sponge |
Cytotoxic | Wyche et al., |
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Peptidolipins | Symbiont to ascidian |
Antibacterial | Wyche et al., |
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Anthracyclinones | Symbiont to tunicate |
Cytotoxic | Sousa et al., |
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Halomadurone | Symbiont to ascidian |
Active against neurodegenerative diseases | Wyche et al., |
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Solwaric acids | Symbiont to ascidian, |
Antibacterial | Ellis et al., |
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Forazoline A | Symbiont to ascidian, |
Antifungal | Wyche et al., |
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Rifamycins | Symbiont to sponge, |
Antibacterial | Kim et al., |
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Saccharothrixmicines | Symbiont to marine mollusk |
Antibacterial, Antifungal | Kalinovskaya et al., |
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Retimycin | MS/MS spectrum pattern based genome mining | Cytotoxic, Antibacterial | Duncan et al., |
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Thiolactomycin | Antibiotic resistance gene based genome mining, heterologous expression | Bacterial fatty acid synthase inhibitor | Tang et al., |
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Lomaiviticin | Bioactivity guided genome mining | Cytotoxic | Kersten et al., |
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Salinosporamide K | Genome mining, metabolomics and transcriptomics | Cytotoxic | Eustáquio et al., |
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Taromycin | BCG Genome mining, heterologous expression | Antibacterial | Yamanaka et al., |
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Enterocin | BCG Genome mining, heterologous expression | Antibacterial | Bonet et al., |
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Fluostatins | Heterologous expression | Antibacterial | Yang et al., |
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Thiocoraline | Heterologous expression | Cytotoxic | Lombó et al., |
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Bromosalinosporamide | Precursor directed biosynthesis | Cytotoxic | Lam et al., |
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Salinosporamide A | Precursor pathway modulation | Cytotoxic | Lechner et al., |
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Salinosporamide X1, Salinosporamide X2 | Combinatorial biosynthesis | Cytotoxic | McGlinchey et al., |
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Salinosporamide X3 | Mutasynthesis | Cytotoxic | Nett et al., |
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Salinosporamide X4 | ||||
Salinosporamide X5 | ||||
Salinosporamide X6 | ||||
Salinosporamide X7 | ||||
Fluorosalinosporamide | Mutasynthesis | Cytotoxic | Eustáquio and Moore, |
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Salinosporamides analogs | Chemobiosynthesis | Cytotoxic | Liu et al., |
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Salinosporamide A | Total chemical synthesis | Cytotoxic | Reddy et al., |
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Homosalinosporamide | Total chemical synthesis | Cytotoxic | Nguyen et al., |
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Salinosporamides analogs | Chemobiosynthesis | Cytotoxic | Liu et al., |
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Salinosporamide E | Semi-synthesis | Cytotoxic | Macherla et al., |
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Bromosalinospramide | ||||
Iodosalinosporamide, Azidosalinosporamide, Hydroxysalinosporamide | ||||
Methylsalinosporamide | Semi-synthesis | Cytotoxic | Manam et al., |
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Tosylsalinosporamide | ||||
Dansylsalinosporamide | ||||
Hydroxysalinosporamide | ||||
Flurosalinosporamide |
Though isolation and cultivation of marine rare actinobacteria is difficult, the development of novel and facile bacterial cultivation platforms such as hollow-fiber membrane chamber (HFMC) and iChip for
It is assumed that strain divergence (phylogenetic or ecological) can have great impact on metabolism and biosynthetic pathway and result in novel chemistry and bioactivities, so research is focused on previously unexplored strains (Monciardini et al.,
Identification of target strains/molecules,
Systematic enrichment of production,
Explicit modification for functional/structural diversity.
Identification of target strains/molecules
The accessible diversity of useful microbial molecules have almost been exhausted by traditional approaches, hence it is speculated that unstudied marine rare actinobacteria can provide reservoir of new microbial molecules (Schorn et al.,
The prime focus in drug discovery is identification of new bioactive chemical or discovery of previously unreported biological activity with known chemical structure. High throughput screening (HTS) can provide easy means for evaluating desired bioactivities against an array natural products (Monciardini et al.,
The next focus in drug discovery is understanding the biogenesis of bioactive molecule in producer strains. The rapid development of genome sequencing methods has revolutionized such studies by unveiling information about the whole genome architecture (Figure
Systematic enrichment of production
Generally, genome information is the starting point for pathway discovery. Various “omics” based tools have been employed for engineering pathways for secondary metabolite production in various actinobacteria (Chaudhary et al.,
Synthetic biology is particularly focused on precise design and construction of new biological systems (metabolic pathways or genetic circuits) that are not prevalent in nature (Andrianantoandro et al.,
Explicit modification for functional/structural diversity
Fundamentally, engineering or modulating the precursor pathways can lead to enhancement or diversification of natural products (Dhakal et al.,
The advent of combinatorial synthetic chemistry has created huge excitement in the pharmaceutical industry by generating libraries of millions of compounds which could be screened by HTS (Butler,
Different approaches for enhancing natural product discovery from marine rare actinobacteria.
As evident from examples above, the innovative methods for procurement of bioactive molecules from potent strains, efficient production and/or modifications by biological and chemical methods can assist in harnessing the full potential of biomolecules derived from marine rare actinobacteria. Further, tuning of structural and functional properties based on structure activity relationship studies can lead to development of superior analogs. But the prime focus should be on application of cutting edge translational research, such as transferring the achievements of discovery or synthesis of such biomolecule to the industrial bench-tops and clinics. The successful collaboration between biologists/chemists in academics and/or pharmaceutical companies can open new avenues for development of highly effective drugs. Salinosporamide A (
DD, ARP, BS, and JS made substantial, direct, and intellectual contribution to the work, and approved it for publication with full consent.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (NRF-2017R1A2A2A05000939).