Marine actinobacteria: an important source of bioactive natural products

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1 Marine actinobacteria: an important source of bioactive natural products Presented by Akram Najafi

2 Marine actinobacteria Actinobacteria are a group of Gram positive bacteria. They can be terrestrial (soil) or aquatic (freshwaters). Form of a very few colonies Cannot grow under laboratory conditions They can be isolated from: - Seashores - Coastal waters - Bottom sediments - Fishes - Molluscs - Sponges - Seaweeds - Mangroves

3 Problem! In spite of the improvements being made in the cultural methods for the isolation of rare marine actinobacteria, many of these organisms still remain unculturable and have to be detected by using molecular techniques. Metagenomic methods, therefore will be useful for characterizing microbes that cannot be cultivated and can also be used to isolate their genes.

4 The most important roles: Marine actinobacteria are the most economically and biotechnologically priceless prokaryotes. Actinobacteria, have potential to : - Produce novel, bioactive natural products - Produce pharmaceutically active secondary metabolites. - Produce 70% of the naturally derived compounds that are currently in clinical use. The important role of marine actinobacteria: - Antimicrobial - Anticancer - Antithrombotics - Antiviral - Antifungal - Insecticidal - Enzyme inhibitory activities - Growth promoting substances

5 The most important genera: The major producers of commercially important bioactive natural products: Streptomyces Actinomadura Actinoplanes Amycolatopsis Marinispora Micromonospora Nocardiopsis Saccharopolyspora Salinispora Verrucosispora In fact, the genus Streptomyces alone accounts for a remarkable 80% of the actinobacterial natural products reported to date.

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7 Sediments and sponges are the most studied marine samples for actinomycetes isolation. The production of most antibiotics is species specific, and these secondary metabolites are important for Streptomyces species in order to compete with other microorganisms that come in contact, even within the same genre.

8 The history of antibiotics derived from Streptomyces began with the discovery of streptothricin in 1942, and with the discovery of streptomycin in Today, 80% of the antibiotics are sourced from the genus Streptomyces, actinomycetes being the most important.

9 Indeed, each strain of actinobacteria is likely to have the genetic potential for the production of secondary metabolites About 23,000 antibiotics have been discovered from microorganisms. It has been estimated that approximately 10,000 of them have been isolated from actinobacteria.

10 Actinomycete-derived antibiotics The most important antibiotics in medicine: - Aminoglycosides - Anthracyclines - Chloramphenicol - Macrolide - Tetracyclines

11 Different types of antibiotic groups Polyketides Peptides Quinones Macrolides Terpenes Alkaloids Indole compounds Pyrroloiminoquinone Butenolides Esters Benzoxazole Piericidins Methylpyridine Trioxacarcins Marinopyrroles Manumycin derivatives Triazolopyrimidine Macrocyclic lactam Sisomicin

12 Novel secondary metabolites produced by marine actinobacteria

13 Antibacteria Activity

14 Abyssomicin C: A novel polycyclic polyketide antibiotic. Inhibitor of para-aminobenzoicacid biosynthesis = inhibits the folic acid biosynthesis = synthetic sulfa drugs. Abyssomicin C possesses potent activity against Gram positive bacteria. Diazepinomicin: Is an unique farnesylated dibenzodiazepinone. It possesses antibacterial, antiinflammatory, antitumor activity. It has a broad spectrum of in vitro cytotoxicity In vivo activity against glioma, breast and prostate cancer in mouse models.

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16 Caboxamycin: It showed inhibitory activity against Gram positive bacteria. Inhibitory activity against the tumor cell lines gastric adenocarcinoma (AGS), hepatocellular carcinoma (Hep G2) and breast carcinoma cells (MCF7) and enzyme phospho diesterase.

17 Anticancer

18 Salinosporamide A: An anticancer and antimalarial drug. A novel rare bicyclic beta-lactonegamma-lactam. An orally active proteasome inhibitor that induces apoptosis in multiple myeloma cells. It is interesting to note that chloroquine resistant strains are still sensitive to Salinosporamide A. Targeting the proteasome system has a huge therapeutic implication as it can restrain growth and survival of most cell types.

19 Cytotoxic activity

20 Antitumor activity Marinomycins: Significant antimicrobial activities against: - Drug resistant bacterial pathogens - Selective cancer cell cytotoxicities against six of the eight melanoma cell lines in the National Cancer Institute s 60 cell line panel.

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25 Recent investigations using enrichment techniques, new selection methods and media have led to the isolation of novel actinomycetes from sediment samples. Improved recovery yields of marine actinomycetes from sponges using nutrient supplements and enzymes have been reported These recent successes are the first step in the right direction. Further development work in improving isolation strategies in the recovery of marine actinomycetes is of utmost importance for ensuring success in this area.

26 Conclusion It seems likely that two major parallel approaches will be developed for drug discovery from marine acti-nobacteria. One will be based on establishment of new and further development of existing isolation and cultivation techniques, to increase the diversity of cultivable isolates, shorten the time of cultivation to achieve appreciable cell mass for higher yields and production of secondary metabolites. As the actinobacteria are very diverse and each species might have special requirements not only for growth, but also for the production of secondary metabolites, this approach will require considerable novel and innovative efforts. Its major advantage is that, if successful, it will result in the production of a compound whose structure, novelty and biological activity can be assessed straight away.

27 Thank you for your attention