MEDICAL MICROBIOLOGY

LECTURE 9. PRESENT & FUTURE MEDICAL APPLICATIONS OF MICROBIAL EXOPOLYSACCHARIDES

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Intoduction

Exopolysaccharides (EPS) -extracellular carbohydrate polymers:

• Produced and secreted by microorganisms, which accumulate outside the cells.
• Capable to be released into the surrounding environment.
• Despite their monomeric composition, similar to well-known plant or animal products
• EPS of different microbial origin (bacteria and fungi) display a large variety of structural combinations (unique properties).
• Microbial production shows several advantages over plant- or macro algae-derived products, such as defined and reproducible production parameters to circumvent environmental influences, and obtain a high quality of the final product.
• Additionally, much higher production titers can be obtained as compared to polysaccharides extracted from plants.

Aim of the review

Achieving a useful insight in the domain, and at clearly distinguishing, in their historical development, the current commercial applications of EPS – officially acknowledged by worldwide accepted documents of medical authorities, from their promising potential applications – discussed in numerous publications. Such a valuable knowledge was updated and organized according to modern research directions in pharmaceutical science and therapy.

The presented data highlight a real outlook and the necessary steps to enhance the efficiency and maximal exploitation of the scientific progress recorded in the EPS field up to date.

Application

Obtained from easily available, renewable resources, biocompatible and apparently non-toxic, microbial EPS have found a very large field of applications, within which their medical uses play an important role.

Potential application

Micro- and Nanosystems for Sustained Delivery

• EPS, have become highly promising materials in the field of “intelligent drug delivery systems”.
• The ability of such hydrophilic polymers to form hydrogels, cross-linked 3D network structures retaining a large amount of water while remaining insoluble, makes them very useful as drug carriers. They can prolong drug residence and, therefore, its therapeutically usable fraction, thus increasing its bioavailability and permitting lower doses with consequently reduced toxic effects.

Diagnostics

• Polysaccharide-coated nanoparticles used in diagnostics (e.g., quantum dots, magnetic materials, such as iron oxide) could play a key role in medical imaging and also in theranostics (diagnosis and therapy).
• A complete platform of super paramagnetic iron oxide nanoparticles with cross-linked dextran coating (CLIO) – containing large series of multifunctional imaging agents for diagnostic magnetic resonance (DMR), magnetic resonance imaging (MRI), positron emission tomography (PET) imaging, fluorescence molecular tomography (FMT) – has been developed.

Fungal β-Glucans

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Generally, the immunomodulation effect of β-glucans is due to their interactions with macrophage receptors, activating these cells as basic effectors in host defense against bacteria, viruses, parasites, and tumor cells. β-glucans have shown varying activity against sarcomas, mammary cancer, some chemically induced cancers, colon cancer, and some leukemia

Diagnostics

Schizo- and scleroglucans

• The most important representatives of fungal beta-glucans are schizophyllan (SPG) and scleroglucan (SG), neutral EPS produced by Schizophyllum commune and Sclerotium rolfsii
• They are composed by a β-(1→3)-d-glucopyranose backbone which is branched with a single β-(1→6)-d-glucopyranose residue at every third glucose unit. 
• Single or associated with chemotherapeutics, these EPS and their derivatives showed promising antitumor (in sarcoma, carcinomas, bladder tumor, fibro sarcoma, mammary carcinoma, leukemia) and immunopotentiator activities.

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Diagnostics

• Botryosphaeran
• Represents another β-(1→3, 1→6)-glucan (1→3 backbone, 1→6 branched glucose and gentiobiose) and is produced by Botryosphaeria rhodina.
• Botryosphaeran showed anticlastogenic activity in vivo (mice) after cyclophosphamide
• It also exhibited antidiabetic (reducing plasma glucose level in streptozocin-induced diabetic rats by 52%) and hypocholesterolemic activities (total and LDL cholesterol reduced until 27% in hyperlipidemic rats

Diagnostics

Lactic bacterial EPS

• One group of bioactive EPS is represented by those produced by lactic bacteria (LAB).
• A 2-substituted β-(1→3)-d-glucan produced by Pediococcus parvulus 2,6 and a recombinant Lactococcus lactis showed immunomodulation by human macrophage activation in vitro, promoting the production of anti-inflammatory cytokines.

Levans

• Levans represent an EPS group of β-(2→6)-d-fructans with some β-(2→1)-branches synthetized from sucrose by levansucrase, produced by several bacteria, including species of Bacillus, Zymomonas, Halomonas, Pseudomonas, Rahnella, Aerobacter, Erwinia, Streptococcus, Microbacterium.
• The levan produced by a Halomonas smyrnensis strain, especially its oxidized (aldehyde) derivative, showed in vitro anti-cancer activity against human lung , liver, gastric , breast cancer cell line.
• The levan produced by Bacillus licheniformis exhibited hypoglycemic and antioxidant activities, enhanced enzymatic defense, protecting the main organs in alloxan-induced diabetic rats 

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Perspectives

• Microbial EPS offers a very large area of ​​medical applications, more and more exploited, but with too slow rates, given their obvious advantages.
• As to the solid dosage forms they compete with cheaper natural polymers, as well as industrial pulps and manufacturing starches, as well as specific niches (intellectual therapy) that can be related to their economic efficiency, performance technologies.
• As drug-targeting and carriers, EPS nanoparticulate systems present certain advantages over those of chemical synthetic origin, such as biocompatibility and apparent lack of toxicity.
• Recent developments in EPS nanoparticle medical imaging systems could be very useful, having also higher chances to be approved as diagnostics.

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Perspectives & Conclusion

• Obviously, based on all the above-mentioned considerations, the external administration forms with topic action (e.g., wound healing, skin-repair) are likely to be more rapidly approved for and to pass clinical trials, as well as to enter the market, followed by EPS-nanopharmaceuticals which have already shown in vivo promising results, as well as by those which avoid the digestive way.
• EPS nanoparticle systems should use some of their advantages over liposomes (for example, higher stability and universal functionalization) that have already been approved by clinical trials. It is expected that for research purposes in particularly complex areas of great interest, for example, targeting the brain for neurological disorders (stroke, tumors, Alzheimer's disease).
• As for bioactive EPS as a potential therapeutics, their task is to prove, necessarily in vivo, therapeutic advantages over the drugs available on the market, and observe well-known protocols for new drugs. Also, studies related to effective means for synergistic effects should be considered. In the new studies of the mechanisms of molecular biology of action, structural-active relationships will be singled out.
• Nevertheless, important therapeutic areas that have recorded promising results (for example, cancer, diabetes, vaccines) still expect further worldwide research and more active participation of microbial EPS in resources for improving health.

Conflict of Interest Statement

The author states that the study was conducted in the absence of any commercial or financial relationship that could be interpreted as a potential conflict of interest.