Marine Cyanobacteria Source of Pharmaceutical Important Compounds

1. Marine Cyanobacteria Source of Pharmaceutical Important Compounds MBT Lecture 10

2. Cyanobacteria • Cyanobacteria are phylogenetically coherent group of Gram-negative prokaryotes possessing the unifying property of performing oxygenic plant like photosynthesis with autotrophy as their dominant mode of nutrition. • Some of the cyanobacterial species can grow in the dark on organic substrates and others under anaerobic conditions with sulfide as electron donor for photosynthesis. • Certain strains have the ability to fix atmospheric dinitrogen into organic nitrogen-containing compounds mainly nitraits.

3. Over 300 nitrogen-containing secondary metabolites have been reported from the prokaryotic marine cyanobacteria. • A majority of these metabolites are biologically active and are products of either the nonribosomal polypeptide (NRP) or the mixed polyketide- NRP biosynthetic pathways. • Biomolecules of the NRP and hybrid polyketide-NRP structural types are important subsets of natural products utilized as therapeutic agents. • These include the antibiotic vancomycin, the immuno suppressive agent cyclosporine like drugs and the anticancer agent.

4. Sheathed cyanobacterial strains . (a) Chroococcus sp. (1000x) (b) Phormidium sp. (1000x).

5. Anticancer Drugs from Marine Cyanobacteria. • Marine cyanobacterial compounds are found to target tubulin or actin filaments in eukaryotic cells, making them an attractive source of natural products as anticancer agents. M. A. Jordan and L. Wilson, “Microtubules and actin filaments: dynamic targets for cancer chemotherapy,” Current Opinion in Cell Biology, vol. 10, no. 1, pp. 123–130, 1998. • Prominent molecules such as the antimicrotubule agents, curacin A and dolastatin 10, have been in preclinical and/or clinical trials as potential anticancer drug. W. H. Gerwick, L. T. Tan, and N. Sitachitta. Alkaloids: Chemistry and Biology,, 2001. • A synthetic derivative of dolastatin 10 "TZT-1027" was found to be superior to existing anticancer drugs, such as paclitaxel vincristine is currently undergoing Phase I testing for treating solid tumors

6. Anticancer Drugs from Marine Cyanobacteria • Pharmacological studies have also showed the mechanistic novelty of certain molecules, such as Antillatoxin, in modifying the activity of Nav channels. • These cyanobacterial toxins are source of valuable molecular tools in functional characterization of Nav channels as well as potential analgesics and neuroprotectants. • Anti-HIV activity of marine cyanobacterial compounds from Lyngbya lagerheimii and Phormidium tenue. • A massive programme of screening of compond from Cyanobacteria resltsin a compound from marine Oscillatoria laete-virians BDU 20801 that shows anti-Candida activity. An immunopotentiating compound with male antifertility, without being toxic to other systems in a mice model, was found in the extracts ofOscillatoria willei BDU 130511

7. CyanobacterialCyclopeptides as LeadCompounds to Novel Targeted Cancer Drugs • Cyanobacterial cyclopeptides, including microcystins and nodularins, are considered a health hazard to humans due to the possible toxic effects of high consumption. • Microcystins are stable hydrophilic cyclic heptapeptides with a potential to cause cellular damage following uptake via organic anion transporting polypeptides (OATPs). • Their intracellular biological effects involve inhibition of catalytic subunits of protein phosphatase 1 (PP1) and PP2, and glutathione depletion and generation of reactive oxygen species (ROS. • Certain OATPs are prominently expressed in cancers as compared to normal tissues, qualifying MC as potential candidates for cancer drug development. • In targeted cancer therapy, cyanotoxins comprise a rich source of natural cytotoxic compounds with a potential to target cancers expressing specific uptake transporters

8. These are attractive biological features for the development of potential anticancer drugs with specific cellular targets. • Apratoxin A (126) is another potent cytotoxic compound worthy of further biological investigation as anticancer agent due to it mechanism of action in attenuating the FGF (fibroblast growth factor) signaling pathway. • Synthetic analogues based on the scaffolds of these cyanobacterial natural products can be developed for SAR studies as well as lead optimization for drug development • Medically important gamma linolenic acid (GLA) is relatively rich in cyanobacteria Spirulina platensis and Arthrospira sp. which is easily converted into arachidonic acid in the human body and arachidonic acid into prostaglandin E2 • Prostaglandin E2 has lowering action on blood pressure and the contracting function of smooth muscle and thus plays an important role in lipid metabolism

9. Vitamins and enzymes from Cyanobacteria • Cyanobacteria being photoautotrophs have the abilityto photosynthetically transform simple, labelled compoundssuch as into complex organiccompounds. Isotopically labelled cyanobacterial metabolites such as sugars, lipids and amino acids are commerciallyavailable • Some of the marine cyanobacteria appear to be potential sources for large-scale production of vitamins of commercial interest such as vitamins of the B complex group and vitamin E. • The carotenoids and phycobiliprotein pigments of cyanobacteria have commercial value as natural food colouring agents, as feed additives, as enhancers of the color of egg yolks, to improve the health and fertility of cattle, as drugs, and in the cosmetic industries. • Cyanobacteria secrete enzymes that can be exploited commercially. Marine cyanobacteria have been used in large-scale production of enzymes such as beta lactamase, protease and lipas . They also secrete cytein and serine protease inhibitor. • These products can be marketedat low cost since relative biomass production of cyanobacteriais much less expensive than bacteria.

10. Potential Commercial Development of Insecticides, Algaecides, and Herbicides from Cyanobacteria • Potential commercial development of cyanobacterial compounds for nonbiomedical applications, particularly include herbicides, algaecides, and insecticides • Fladmark et al. screened extracts from 76 isolates of cyanobacteria and found several of these isolates produced compounds that were larvicidal to Aedes aegypti. • The greatest inhibition, however, was associated with presence of the hepatotoxic microcystins and the neurotoxic anatoxin-a. • Methanolic extracts from an isolate of Westiellopsis sp. were larvicidal to several species of mosquito, including representatives of Aedes aegypti (a vector forDengue Fever), Anopheles stephensi (a vector for malaria), and Culex tritaeniorhynchus and C. quinquefasciatus (vectors of encephalitis). • The use of genetically engineered cyanobacteria, specifically expressing the insecticidal proteins from Bacillus thuringiensis to control mosquito larvae is also in use.

11. Biofertilizers • Since most species are nitrogen fixing and several of them are soil dwelling, making them an ideal biofertilizers. • Inherent fertility of tropical rice field soils depend on the activity of N2-fixing cyanobacteria. A variety of cyano-bacterial strains colonize rice fields wherein heterocystous species are capable of fixing atmospheric nitrogen. • However,several non-heterocystous cyanobacteria are able to fix atmospheric nitrogen under microaerophilic conditions. •  Insitu estimations using acetylene reduction technique haveshown an addition of 18–15 kg N ha– yr–1 due to the activityof diazotrophic cyanobacteria. • The role of N2 -fixingcyanobacteria in maintenance of the fertility of rice fieldshas been well substantiated and documented all over theworld. In India alone, the beneficial effects of cyanobacteriaon yield of many rice varieties have been demonstrated ina number of field locations

12. Biofertilizers • Beneficial effects of cyano-bacterial inoculation have also been reported on a numberof other crops such as barley, oats, tomato, radish, cotton,sugarcane, maize, chilli and lettuce • The cyano-bacterial symbiont Anabaena-azollae fixes atmospheric nitrogen estimated between 120 and 312 kg N2 per hectare. • Azolla supplies 150–300 tons per hectare per year of green manure, which supports growth of soil microorganisms including heterotrophic N2 fixers

13. Cyanobacteria in waste treatment • Use of Cyanobacteria in waste treatment is beneficial in different ways since they can bring about oxygenation and mineralization, in addition to serving asfood source for aquatic species. • Using the marine cyano-bacteria Oscillatoria sp. BDU 10742, Aphanocapsa sp. BDU 16 and a halophilic bacterium HalobacteriumUS 101, Uma and Subramanian et al., 1997treated ossein factory effluentwhich resulted in reduced calcium and chloride levels and enabled 100% survival and multiplication of Tilapia fishwith only cyanobacteria as feed source. • Phormidium valderianum BDU 30501 was able totolerate and grow at a phenol concentration of 50mg/l and removed 38 mg/l within a retention period of sevendays. • This result opens up the possibility of treating a varietyof phenol containing effluents. The organism was also effec-tive in optimal sorption/desorption of heavy metal ions (Cd2–,Co2–)