Open access peer-reviewed chapter

Microorganisms as Alternative Sources of New Natural Products

Written By

Lucía Ortega Cabello

Submitted: 24 March 2020 Reviewed: 29 April 2020 Published: 27 May 2020

DOI: 10.5772/intechopen.92697

From the Edited Volume

Bioactive Compounds in Nutraceutical and Functional Food for Good Human Health

Edited by Kavita Sharma, Kanchan Mishra, Kula Kamal Senapati and Corina Danciu

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Microbial natural products have become important over the last decades due to the ability of bacteria and fungi to subsist in different habitats such as marine and extreme environments. Microorganisms are able to synthesize new compounds with diverse therapeutic activity equal to or better than the activity of compounds already known, thus being promising for the treatment of different diseases such as cancer or the solution to health problems such as antibiotic resistance. The production of microbial natural compounds can be improved by modifying culture media, growing conditions, amplifying gene expression or by co-cultivation techniques, which are the major challenges in the industrial production of such compounds.


  • microorganisms
  • antioxidants
  • antibiotics
  • antitumor
  • polymers

1. Introduction

The lack of effectiveness in current therapeutics using already known compounds has made necessary the rediscovery of natural products, either for obtaining new compounds or modifying their structure to improve their activity, where plants are the most popular sources.

However, due to seasonal and environmental conditions that influence their production, alternative sources have been searched for. Microorganisms have been considered as good alternative sources due to the self-sustainability and controllable growth conditions such as carbon source, nitrogen source, pH and temperature [12], thus leading to the possibility of discovering new compounds.

In this chapter, we will focus on the uses of microbial secondary metabolites as antioxidants, antibiotics, antitumor and polymers from mainly Streptomyces genus, which have been important in soil bioremediation and biocatalysis for the obtention of enantiopure compounds [3, 4, 5].


2. Microorganisms as sources of natural products

Since the discovery of penicillin and streptomycin in 1928 and 1943 respectively [6, 7], microorganisms have become fascinating alternative sources because of the diversity of natural products with new structures to be elucidated and studied for biological activity.

Microorganisms can be found in very extreme environments (soil/marine, high/low temperature, acid/alkaline) [8], with the isolation of these microorganisms being a major challenge to date because there are uncultivable microbes, complicating natural product discovery. To overcome this problem, different techniques have been applied such as co-cultivation, as well as exploration of isolation techniques on natural habitats [9]. Co-cultivation has attracted attention because it can induce the biosynthesis of new compounds [10] such as libertellenone A, B, C and D from co-cultivating α-proteobacterium and Libertella sp. [11] and stearidonic acid from Rhizobium strain 10II and Ankistrodesmus sp. [12].

Terrestrial fungus and actinobacteria are the most important sources of antimicrobials, cytotoxic compounds and antioxidants, among others [13]. However, in the last few years, marine environment has attracted attention due to the diversity and effectivity of natural products [14], such as apratoxins from cyanobacteria from the Lyngbya genus used as cytotoxic agents to induce apoptosis [15], as well as salinisporamides isolated from Salinispora tropica with activity against human colon carcinoma [16].


3. Antibiotics

The inadequate use of current antibiotics has led to antibiotic resistance, which is a global threat because of the adaptation rate of microorganisms [17]. Natural product discovery as a potential solution to antibiotic resistance has been important if we recall the discovery of penicillin and streptomycin. Nevertheless, actinobacteria isolated from soil have already been widely exploited, limiting the search of new antibiotics [18].

Due to the latter, the need to search new microorganisms associated with higher life forms or from unknown environments such as marine and extreme ecosystems [19, 20], as well as co-cultivation techniques between antagonists strains have been useful [21, 22], as the case of the co-cultivation of a Micromonospora sp. with a Rhodococcus strain to enhance the production of keyicin [23], as well as the co-cultivation of a marine Pestalotia sp. with an unidentified bacteria to obtain pestalone which resulted in high activity against Staphylococcus aureus and Enterococcus faecium [24].

Among the examples of marine microbial sources is a Streptomyces strain isolated from a marine sediment in India that produced ala-geninthiocin along with val-geninthiocin, geninthiocin and staurosporine; all compounds were found to be effective against Staphylococcus aureus and Candida albicans [25]. Another example is tetrahydroanthra-γ-pyrone from marine Streptomyces sp. (isolated from Binzhou shell island), which presented activity against Bacillus subtilis, Staphylococcus aureus and Enterococcus faecalis with a minimum inhibitory concentration (MIC) from 3 to 46 μg/mL [26].

The presence of metals has been explored to increase the production of antibiotics, such as the presence of nickel chloride in the cultivation of Streptomyces pratensis (isolated from the east coast of China), which enhanced the production of angucycline-type antibiotics, with moderate antimicrobial activity against Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli and Staphylococcus aureus with a MIC of 16 μg/mL [27]. Other minerals that have been tested to increase antimicrobial production on other Streptomyces strains are magnesium, calcium, manganese, cobalt, copper and iron salts, where copper sulfate and iron chloride resulted in the best induction of antimicrobial biosynthesis [28].

TheMicromonospora is a genus of actinobacteria known to produce other antibiotics such as aminorifamycins and sporalactams with a good antimicrobial activity against Mycobacterium tuberculosis [29], as well as phocoenamicins with a potent activity against Staphylococcus aureus and Mycobacterium tuberculosis (MIC 32–64 μg/mL); the differences in their activity are attributed to different functional groups in the macrocyclic core [30].

Marine fungi have been considered as antibiotic sources such as Penicillum sp. (isolated from the coast of China), which produced four new compounds (neocitreoviridin, 10z-isocitreoviridinol, penicillstresseol and isopencillstressol) in the presence of cobalt. Penicillstresseol and isopencillstressol presented a MIC of 0.5 μg/mL against Staphylococcus aureus, followed by 10z-isocitroviridinol with a MIC value of 1–4 μg/mL, while neocitreoviridin exhibited a strong activity against Pseudomonas aeruginosa with a MIC around 4 μg/mL [31].

MarineEngyodontium album (isolated from a sponge) produced six new polyketides, where engyodontochone A and engyodontochone B were the ones that exhibited the best antimicrobial activity against Staphylococcus aureus, which was better than that of chloramphenicol [32].

Emerimicin IV extracted from Emericellopsis minima (isolated from a bay in Chile) exhibited a strong antimicrobial activity against Enterococcus faecalis and moderate to low activity against Staphylococcus aureus with a MIC value of 12.5 and 100 μg/mL respectively [33].

Extremophiles have also been useful in the discovery of new antibiotics due to the extreme growth conditions such as salinity (>1.0 M NaCl), pH (<5.0, >8.0), temperature (1–15°C and >45°C) and pressure (380 atm and >500–1200 atm); such conditions can be found on oceans, hypersaline lakes, hot springs and hydrothermal vents, among other places [34]. Actinobacteria are known to survive a range of the conditions previously reviewed such as the ones isolated from Kazakhstan where screening for antagonistic strains against Escherichia coli and Aspergillus niger [35].

Co-cultivation techniques have also been used for antibiotic synthesis such as Penicillium fuscum with Penicillium camemberti/clavigerum, whose co-culture allowed the extraction and purification of new macrolides named berkeleylactones. Berkeleylactone A was the one that exhibited the best activity against Staphylococcus aureus, Bacillus anthracis, Streptococcus pyogenes, Candida albicans and Candida glabrata [36].


4. Antioxidants

Antioxidants are molecules capable of counteracting at low concentrations the damage of mainly reactive oxygen and nitrogen species (ROS and RNS), which are generated from metabolic pathways such as mitochondrial respiratory chain and lipid β-oxidation among others [37, 38]; depending on the ROS/RNS, they can attack different targets [39, 40] whether biomolecules such as proteins, lipids and nucleic acids or cell organelles [22, 41]. Usually ROS and RNS at moderate concentration are useful for defense, signaling mechanisms and cellular maturation [42, 43, 44, 45]; however when ROS and RNS concentration are in excess, different pathologies can be caused due to oxidative stress by causing tissue damage [414345, 46].

In this regard actinobacteria have played their role as potential sources of antioxidants where [47] isolated Streptomyces strains in the Oman sea presented an inhibitory concentration 50 (IC50) that ranges from 356.8 to 566.4 μg/mL against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical inhibition.

Growth media is important for the production of antioxidants such as the case reported by [48] on Streptomyces variabilis (isolated from the Gulf of Khambhat) using six different media: starch casein agar, yeast malt extract agar (ISP2), glycerol asparagine agar (ISP5), inorganic salt agar (ISP4), tyrosine agar (ISP7) and gause’ synthetic agar (GSA), and incubated at 30°C for 7–9 days. GSA medium was selected because there was a larger quantity of cell mass compared to other media; its metabolites were extracted with ethyl acetate and antioxidant activity was tested against DPPH, metal and hydrogen peroxide (H2O2) radical in a concentration range from 0.5 to 2.0 mg/mL. The best radical scavenging activity was against H2O2 radical (64% of antioxidant activity) at a concentration of 0.5 mg/mL.

Specific radical scavengers can be obtained depending on the microorganism such as the strain of Streptomyces antioxidans (isolated in the forest of Tanjung Lumpur), in a research reported by [49], which exhibited 79.84% of antioxidant activity against superoxide radical at an extract concentration of 1.5 mg/mL; most compounds present in the extract were pyrazines, fatty acids and a phenolic compound. Similar compounds have been found by [50] in a strain of Streptomyces monachensis isolated from a mangrove in Malaysia with an antioxidant activity against superoxide radical as well as metal chelating activity of 83.80 and 75.50% respectively.

Among other antioxidants found on microorganisms extracted due to their possible coloring properties are carotenoid pigments mainly used as vitamins in the case of carotenes and xanthophylls, which can be found on bacteria (Gordonia rubropertincta), yeast (Blakeslea trispora) and microalgae (Haematococcus pluvialis) [51].

In this regard, 50 carbon atom carotenoids identified as bacterioruberin derivatives have been detected as main pigments of Haloterrigena turkmenica grown in halobacterium medium, which were tested with DPPH and ferric reducing antioxidant power (FRAP) assays [52].

As mentioned earlier, growth media can influence in the production of antioxidants. Three yeasts isolated from Brazil were tested in different media. The highest carotenoid producer was Rhodotorula mucilaginosa in malt and yeast extract medium (MYM) followed by glycerol and corn steep liquor (GCSLM) with a biomass production of 13.5 and 7.9 g/L and a carotenoid content of 1068.5 and 224.8 μg/L respectively.

The authors noticed changes in the carotenoid profile with a higher content of β-carotene followed by astaxanthin and lutein in MYM (91.8, 6.9 and 1.3% respectively). With GCSLM, astaxanthin and lutein content increased (23.3 and 71.2% respectively) and β-carotene content decreased (71.2%).

This change in the carotenoid profile influenced greatly in the antioxidant activity where the pigments presented antioxidant activity against DPPH, 2.7 and 14.7% for MYM and GCSLM respectively. A similar, yet higher behavior was observed with 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and FRAP [53]. The increase in antioxidant activity could be due to the increase of xanthophyll content since the presence of oxygenated moieties in the carotenoid structures increases the antioxidant activity [54].

Similar experiments have been carried out by adding bivalent ions such as ferrous, calcium, copper and zinc among others as initiators of the Fenton reaction or as cofactors for carotenoid biosynthesis [55, 56, 57]. However, in a research reported by [58], such behavior was not observed on carotenoid pigments from marine strains of Rhodococcus and Gordonia genera (isolated from the Gulf of Mexico). However, a change in the carotenoid profile was observed on Rhodococcus sp., which may improve the antioxidant activity for two reasons:

  1. The increase on the selective carotenoids that may present the best antioxidant activity [58].

  2. The possible formation of carotenoid-metal complexes, mainly in the oxygenated groups [59].

These carotenoids were identified as glycosidic carotenoids; such carotenoid extracts demonstrated a better antioxidant activity against DPPH radical (IC50 of 1.07 and 0.09 μg/mL for Rhodococcus sp. and Gordonia sp. respectively) than β-carotene (IC50 of 19.59 μg/mL) [60]. Furthermore, these extracts were compared against those reported by [61] where the authors calculated an IC50 of 11.6 and 9.1 μg/mL for carotenoid extracts from two varieties of Bactris gasipae, presenting a better antioxidant activity than the bacterial extracts.

Some of these microbial carotenoid pigments are already commercially available for their use as supplement like Lycogen™, which is a carotenoid pigment from a mutant strain of Rhodobacter sphaeroides [62], which contains spheroidenone, bixin (a carotenoid found on Bixa orellana L.) and hydroxyspheroidenone [63, 64]. Another pigment that is already available is astaxanthin from microalgae Haematococcus pluvialis, whose production cost is estimated at $552/Kg, being competitive with synthetic carotenoids ($1000/Kg) [65].


5. Antitumor

Tumoral cells are submitted to high levels of ROS and RNS, manifesting uncontrolled proliferation, death evasion, angiogenesis, invasiveness and metastasis, causing loss of cellular function due to changes in the DNA [66].

The action of ROS and RNS may trigger different factors that stimulate angiogenic processes such as the vascular endothelial growth factor inducing proliferation, migration and tubule formation [67], as well as the induction of epithelial-mesenchymal transition by upregulation of transforming growth factor β [68].

In this regard, antioxidants serve as chemopreventive agents on healthy tissue while increasing the damage on cancerous cells; this phenomenon has been studied on secondary metabolites of plant origin such as soy isoflavone, and polyphenols such as resveratrol and hydroxychalcones [69].

Among microbial compounds that presented a correlation between antitumor and antioxidant activity were in extracts of Streptomyces malaysiense with compounds identified as pyrrolizidines and deferoxamine, exhibiting antioxidant as well as antitumor activities. Deferoxamine, which is listed in the World Health Organization’s List of Essential Medicines, presents antioxidant activity by chelating iron and antitumoral activities [70].

Another interesting example of antitumoral compounds is an already known compound that is widely used for breast cancer stage III and IV treatment, which is doxorubicin [71], isolated from a mutant strain of Streptomyces peuceticus. Doxorubicin works as a DNA intercalating agent by inhibiting the activity of topoisomerase II in DNA replication [72].

Since the 1950s there has been an increase in the interest of studying marine microbial sources for drug discovery in the area of anticancer drugs such as tetracenoquinocin and 5-iminoarianciamicina, extracted from Streptomyces sp. in 2010, which were effective against human cervical carcinoma HeLa cells and myelogenous leukemia LH-60 [73].

A similar case is the research reported by [74], where they isolated 32 strains from lagoon sediment in Lagos. The strains were identified mostly as Streptomyces and Micromonospora. Nine isolates from Streptomyces genus presented cytotoxic activity against human acute myelocytic and promyelocytic leukemia, cervical carcinoma, human gastric, breast adenocarcinoma cell lines varying their effectiveness at a concentration below 1 mg/mL. The compounds present in the extracts were identified as kigamicin and staurosporine analogues.

Other kind of compounds found in Streptomyces strains are pyrrolopyrazines (found on Streptomyces colonosanans), which presented anticancer activity against human colon cancer cell lines [75].

Diketopiperazines from Streptomyces nigra (isolated from a mangrove soil) were effective against several human cancer-derived cell lines, while with normal cell lines they were inactive at a concentration range of 50–100 μg/mL. Other compound found on Streptomyces nigra was β-carboline, which is a compound widely found in plants with anticancer activity against a variety of cancer cell lines that act inhibitis DNA topoisomerase as well as intercalates in the DNA strands, changing the DNA structure; and tamoxifen [76] which is commonly used to control breast cancer after chemo and radiotherapy have been applied to the patient.

Another actinobacteria with discovered antitumor activity is Rhodococcus, where [77] a Rhodococcus strain was isolated from a contaminated soil. The extract exhibited cytotoxic activity against HepG2 and Hela cell line with an IC50 of 33 and 73 μg/mL respectively.

Another class of compounds that exhibit antitumor properties are polysaccharides, which inhibit cell growth and induce apoptosis as well as exert a synergistic effect with other chemotherapeutical agents such as doxorubicin [78], such as that reported on resveratrol [79, 80]. Examples of these kind of compounds are exopolysaccharides (EPs) produced by Bacillus mycoides composed of a sugar mixture containing galactose, mannose, glucose and glucuronic acid; such EPs exhibited antitumor activity by observing morphological abnormalities in HepG2 and Caco-2 cancer cell lines with an IC50 of 138 and 159 μg/mL respectively, while on normal cells the IC50 was 245 μg/mL [81]. A similar activity was observed with Bacillus licheniformis EP constituted by glucose, galactose, fructose, mannose and galacturonic acid on MCF cancer cell lines with an IC50 value of 840 μg/mL [82].

It can be observed from both Bacillus species that changes in the polysaccharide composition may influence the antitumor activity; as observed by [83] in three EPs of Streptococcus thermophilus, two of them were mainly composed by mannose, while the other contained mainly glucose with a protein moiety. The latter exhibited a higher antitumor activity on HepG2 cells with an IC50 of 313.75 μg/mL, while for the other two compounds the antitumor activity was below 50%.

Some Trichoderma species are also able to synthesize EP constituted by mannose, glucose, galacturonic acid and glucuronic acid with a mannan core, where the antitumor activity was more effective on HeLa cells than on MCF-7 cells by arresting G2/M phase and inducing apoptosis [84].

Fungal endophytes are another kind of microorganisms that could be used as alternative sources of bioactive compounds found in plants. Such as taxol (a chemotherapeutic), pestalactams and penicestorids. Taxol was discovered initially on Taxus brevifolia, and it presents a similar activity as doxorubicin [85]. Another example, camphotecin, found commonly on Campotheca acuminata, was also found on Fusarium solani. Camphotecin from Fusarium solani was proved to induce apoptosis on Vero cells at a concentration of 30 μg/mL for 24 h with a maximum apoptosis of 15% [86].

Endophytic fungi are also able to produce EP with antitumor activity. An example is Bionectria ochroleuca whose activity was proved to be effective against liver, gastric and colon cancer cell lines in a concentration range from 100 to 450 μg/mL without exhibiting toxicity in healthy cells [87].

Fungal co-cultivation techniques have also been used in the obtention of antitumor compounds. For example, Isaria felina with Aspergillus sulphureus was used for obtaining oxirapentyn L, which exhibited antitumor activity at IC50 greater than 100 μg/mL [88].


6. Polymers

Biopolymers such as lipopolysaccharides (LPSs), EP and extracellular polymeric substances (EPSs) are high-molecular weight substances secreted by microorganisms [89]. In the case of EP, their antitumor properties have been observed in some bacteria as well as in endophytic fungi. EPSs are exopolymers, constituted by polysaccharides, lipids, proteins and nucleic acids; the composition provides these biopolymers unique properties that can be manipulated for a variety of technological applications [90].

LPSs from Gram negative bacteria possess a lipid moiety and a glucosamine fraction with phosphate groups to improve membrane stability [91, 92]. Some of these LPSs have been studied as flocculating and emulsifying agents; for example, the one produced by Trichosporon mycotoxinivorans at a concentration of 8.6 mg/mL was able to flocculate kaolin and charcoal with 80 and 78% of efficiency respectively, while the emulsifying activity by mixing water and kerosene presented an emulsification efficiency of 81% [93].

Another application of LPSs is to enhance the immune response by accelerating the maturation of dendritic cells using immobilized LPS nanostructures; compared to LPS solutions and LPS monolayers, such structures could be useful in HIV patients [94]. In a similar manner, inactivated LPSs from non-sulfur photosynthetic bacteria have been used to stimulate immune response [95].

EPs have become important in material science, being useful as storage molecules, protective capsular layers and as matrix components of biofilms due to their water-binding capacity because of hydroxyl and carboxyl groups. EPs can be used in drug delivery, enzyme immobilization, tissue engineering, among other uses [96], their production depends on composition and growth conditions applied on the culture media [97].

EPs from lactic acid bacteria have been used as emulsifiers and viscosifiers because of their pseudoplastic rheological behavior; the sugar identified have been dextran, reuteran, levan and insulin, pullulan (homopolysaccharides), kefiran and hyaluronic acid (heteropolysaccharides) among others depending on the strain used to produce EP [98, 99].

An example of this kind of EP is levan produced by Bacillus licheniformis reported by [100] where the authors studied its physicochemical properties and concluded its utility in stabilizing topical formulations. Other uses that have been studied of levan but from Halomonas smyrnensis were on tissue engineering and prosthetics [101].

Hyaluronic acid from Streptococcus equi was compared against kefiran isolated from kefir grains (also produced on lactic acid bacteria) demonstrating antioxidant and immunostimulatory activities [102].

Marine EPs are mainly heteropolysaccharides composed of pentoses, hexoses, aminosugars or uronic acids [103]. The EPs of Pantoea sp. [97] presented wound healing activity by facilitating cell migration on fibroblasts. The EPs of Bacterium polaribacter increased 1.42-fold the wound closure at an EP concentration of 1 mg/mL.

EPS in microbial cells aids in the fixation to marine surfaces, thus forming biofilm communities though a three-dimensional arrangement in which the cells can localize extracellular activities and conduct agonist/antagonist interactions. In marine bacteria, EPSs generally contain higher levels of glucuronic and galacturonic acids. Among the sugars found on EPSs are glucose, galactose, mannose, fructose, rhamnose, uronic acids, N-acetyl-glucosamine and N-acetyl-galactosamine; the protein moiety can occur as peptides, aminosugars, glycoproteins, proteoglycans and amyloid proteins. Proteins can occur as peptides, aminosugars, glycoproteins, proteoglycans and amyloid proteins. Extracellular DNA and extracellular nucleases can be found, thus influencing on the physical consistency [90].

EPS production depend on the presence of divalent cations [90], as it is in the case of Bacillus vallismortis; which EPS was better in composition in the presence of zinc enhancing the adsorption capacity [104]; while in the presence of the ferric ion the EPS production is limited [90].

An application of EPS is in microencapsulation of vitamins to formulate functional foods as demonstrated on Cyanoteche sp. The authors extracted its EPSs and made encapsulation tests of vitamin B12 either alone or in the presence of arabic gum by spray-drying technique. EPS alone presented a particle diameter of 8 μm and when combined with arabic gum the particle diameter was smaller than that of EPS alone; both microcapsules presented different release kinetics due to the different swelling mechanisms of the EPS [105]. EPS from another Cyanoteche strain was found to be useful for controlled delivery of small molecules such as procainamide as well as proteins. The authors found out that adding bivalent cations such as Ca2+, as well as considering the protein charge, the release kinetics could improve [106].

Other encapsulation studies were performed on the EPSs of Bacillus subtilis in the preservation of Lactobacillus plantarum as probiotic, facilitating its survival in gastric conditions during co-cultivation of both strains [107].

EPSs have been widely used in sludge treatment for pharmaceutically active ingredients removal such as ciprofloxacin as well as sulfonamides. EPS from Klebsiella sp. was tested against sulfonamides; the high protein content of EPS (mainly tryptophan and tyrosine) is a critical factor in the adsorption of sulfonamides for hydrophobic interactions with sulfonamides [108]. The same thing happens with ciprofloxacin being important to reach the isoelectric point of the protein moiety as well as the use of iron salts to enhance the adsorption of ciprofloxacin [109, 110, 111].

The latter ability of EPSs to adsorb antibiotics needs further studies in order to model and improve the kinetics of controlled release dosage forms giving us a natural and possible biocompatible alternative material for design of molecular pharmaceutical forms.


7. Challenges and trends in the discovery and development of microbial natural products

Even though the plethora of natural products of microbial origin mainly isolated from marine and extreme environments is a large field of research, developments in technological aspects such as the increase in natural product production for industrial scale-up or overcoming the difficulty in isolating microorganisms are needed [112].

Genome mining focused on the activation of silent genes, to search gene clusters serving as molecular markers, with complementary informatic tools has been a solution [113, 114]. This technique can be used in metabolic engineering, producing an heterologous host through genetic engineering, using plasmids or recombinant systems using interspaced palindromic repeat, one of the most recent techniques applied in genetic engineering [115].

Another trend also used on unculturable microorganisms is the discovery of environmental DNA coupled to cosmids for gene expression, which have also been used for the selective isolation of biologically active natural products [116].

Search of ideal media and culture conditions have also been a major challenge in optimizing the amount of metabolite present on the microorganism, which have been developed by either trial and error or statistical design [116]; an example is the presence of metallic salts to activate enzymes involved in the biosynthetic route or by manipulating temperature, light, aeration and pH [117] as we saw in the obtention throughout the chapter [117].

Another technique widely observed along the chapter was co-cultivation technique between bacteria, fungi or in combination to improve metabolite production.

Conventionally organic solvents are often used for natural product extraction, which is an important step for industrial scale-up [118, 119]. However, due to the health and environmental hazards, alternative extraction techniques have been searched for with the purpose of reducing residues and thus environmental impact [119, 120]. Among the alternative extraction techniques are ultrasound, microwave, enzyme and pulse electric field. The latter techniques have been widely explored on plants; nevertheless, on microorganisms, they have been poorly explored, thus representing a critical challenge in natural product research [121, 122].

The possibility to expand the research in this regard, is also the search of alternative solvents such as supercritical fluids, [119, 120], ionic liquids, gas-expanded liquids and vegetable oils [121, 122, 123].


8. Conclusions

Microbial natural products are a wide research field with much potential to be explored, the main goals being:

  1. Isolating new microorganisms, being successful in marine as well as extreme environments, including genetic diversity studies for unculturable microorganisms.

  2. Screening of isolates with potential biological activity, by performing extractions of different polarity to begin the selectivity of compounds.

  3. Extraction and purification for identification of active compounds, where new extraction techniques can be explored such as supercritical fluids, microwave, enzyme, among others to make the discovery process more eco-friendly.

  4. Elucidation of action mechanisms of new active compounds through in silico studies, for considering the possibility of improving the activity.

  5. Improvement of natural compounds production for industrial scale-up, as it has already been seen that these are the main challenges and trends through alternative techniques such as co-cultivation, genome mining and media formulation, the last one being the first approach for production enhancement.

  6. Preclinical and clinical trials of microbial natural products with already discovered potential activity, to determine biocompatibility and innocuousness of compounds such as EPs and EPSs for antitumoral activity as well as tissue engineering.

As it can be seen, there is a long way ahead in natural product discovery that could solve many health and environmental issues such as antibiotic resistance, cancer, soil and water contamination, tissue engineering, among other contributions.



The author thanks the Department of Biological Systems for their support.


  1. 1. Sen T, Barrow CJ, Deshmukh SK. Microbial pigments in the food industry—Challenges and the way forward. Frontiers in Nutrition. 2019;6:1-14. DOI: 10.3389/fnut.2019.00007
  2. 2. Saini RK, Keum YS. Microbial platforms to produce commercially vital carotenoids at industrial scale: An updated review of critical issues. Journal of Industrial Microbiology & Biotechnology. 2019;46(5):657-674. DOI: 10.1007/s10295-018-2104-7
  3. 3. Guimarães TC, Gomes TS, Fernandes CD, Barros FD, Oliveira KV, Bilal M, et al. Antitumor microbial products by actinomycetes isolated from different environments. In: Arora PK, editor. Microbial Technology for Health and Environment. Singapore: Springer; 2020. pp. 113-160. DOI: 10.1007/978-981-15-2679-4_5
  4. 4. Chaturvedi S, Khurana SMP. Importance of actinobacteria for bioremediation. In: Khurana S, Gaur R, editors. Plant Biotechnology: Progress in Genomic Era. Singapore: Springer; 2019. pp. 277-307. DOI: 10.1007/978-981-13-8499-8_13
  5. 5. Anteneh YS, Franco C. Whole cell actinobacteria as biocatalysts. Frontiers in Microbiology. 2019;10:77. DOI: 10.3389/fmicb.2019.00077
  6. 6. Gaynes R. The discovery of penicillin—New insights after more than 75 years of clinical use. Emerging Infectious Diseases. 2017;23(5):849-853. DOI: 10.3201/eid2305.161556
  7. 7. Woodruff HB. Selman A. Waksman, winner of the 1952 Nobel prize for physiology or medicine. Applied and Environmental Microbiology. 2014;80(1):2-8. DOI: 10.1128/AEM.01143-13
  8. 8. Huang T, Lin S. Microbial natural products: A promising source for drug discovery. Journal of Applied Microbiology and Biochemistry. 2017;1(2):5. DOI: 10.21767/2576-1412.100005
  9. 9. Ma K, Kim SD. Development of techniques for isolating microorganisms. Enliven Archive. 2018;5(1):1-5
  10. 10. Arora D, Gupta P, Jaglan S, Roullier C, Grovel O, Bertrand S. Expanding the chemical diversity through microorganisms co-culture: Current status and outlook. Biotechnology Advances. 2020;40:107521. DOI: 10.1016/j.biotechadv.2020.107521
  11. 11. Oh D-C, Jensen PR, Kauffman CA, Fenical W. Libertellenones A–D: Induction of cytotoxic diterpenoid biosynthesis by marine microbial competition. Bioorganic & Medicinal Chemistry. 2005;13(17):5267-5273. DOI: 10.1016/j.bmc.2005.05.068
  12. 12. Do Nascimento M, Dublan MLA, Ortiz-Marquez JCF, Curatti L. High lipid productivity of an Ankistrodesmus-Rhizobium artificial consortium. Bioresource Technology. 2013;146:400-407. DOI: 10.1016/j.biortech.2013.07.085
  13. 13. Demain AL. Importance of microbial natural products and the need to revitalize their discovery. Journal of Industrial Microbiology & Biotechnology. 2014;41:185-201. DOI: 10.1007/s10295-013-1325-z
  14. 14. Torregrosa-Crespo J, Montero Z, Fuentes JL, Reig García-Galbis M, Garbayo I, Vílchez C, et al. Exploring the valuable carotenoids for the large-scale production by marine microorganisms. Marine Drugs. 2018;16(6):203. DOI: 10.3390/md16060203
  15. 15. Russo P, Cesario A. New anticancer drugs from marine cyanobacteria. Current Drug Targets. 2012;13:1048-1053. DOI: 10.2174/138945012802009035
  16. 16. Williams PG, Buchanan GO, Feling RH, Kauffman CA, Jensen PR, Fenical W. New cytotoxic salinosporamides from the marine actinomycete Salinispora tropica. The Journal of Organic Chemistry. 2005;70(16):6196-6203. DOI: 10.1021/jo050511+
  17. 17. Ferri M, Ranucci E, Romagnoli P, Giaccone V. Antimicrobial resistance: A global emerging threat to public health systems. Critical Reviews in Food Science and Nutrition. 2017;57(13):2857-2876. DOI: 10.1080/10408398.2015.1077192
  18. 18. Moore BS, Carter GT, Brönstrup M. Are natural products the solution to antimicrobial resistance? Natural Product Reports. 2017;34(7):685-686. DOI: 10.1039/C7NP90026K
  19. 19. Niu G, Li W. Next-generation drug discovery to combat antimicrobial resistance. Trends in Biochemical Sciences. 2019;44(11):961-972. DOI: 10.1016/j.tibs.2019.05.005
  20. 20. McSorley FR, Johnson JW, Wright GD. Natural products in antibiotic discovery. In: Fong IW, Shlaes D, Drlica K, editors. Antimicrobial Resistance in the 21st Century. Cham: Springer; 2018. pp. 533-562. DOI: 10.1007/978-3-319-78538-7_17
  21. 21. Ueda K, Beppu T. Antibiotics in microbial coculture. The Journal of Antibiotics. 2017;70(4):361-365. DOI: 10.1038/ja.2016.127
  22. 22. Netzker T, Flak M, Krespach MK, Stroe MC, Weber J, Schroeckh V, et al. Microbial interactions trigger the production of antibiotics. Current Opinion in Microbiology. 2018;45:117-123. DOI: 10.1016/j.mib.2018.04.002
  23. 23. Adnani N, Chevrette MG, Adibhatla SN, Zhang F, Yu Q , Braun DR, et al. Coculture of marine invertebrate-associated bacteria and interdisciplinary technologies enable biosynthesis and discovery of a new antibiotic, keyicin. ACS Chemical Biology. 2017;12(12):3093-3102. DOI: 10.1021/acschembio.7b00688
  24. 24. Cueto M, Jensen PR, Kauffman C, Fenical W, Lobkovsky E, Clardy J. Pestalone, a new antibiotic produced by a marine fungus in response to bacterial challenge. Journal of Natural Products. 2001;64:1444-1446. DOI: 10.1021/np0102713
  25. 25. Iniyan AM, Sudarman E, Wink J, Kannan RR, Vincent SGP. Ala-geninthiocin, a new broad spectrum thiopeptide antibiotic, produced by a marine Streptomyces sp. ICN19. The Journal of Antibiotics. 2019;72(2):99-105. DOI: 10.1038/s41429-018-0115-2
  26. 26. Han Y, Wang Y, Yang Y, Chen H. Shellmycin A-D, novel bioactive tetrahydroanthra-γ-pyrone antibiotics from marine Streptomyces sp. shell-016 Marine Drugs. 2020;18(1):58. DOI: 10.3390/md18010058
  27. 27. Akhter N, Liu Y, Auckloo BN, Shi Y, Wang K, Chen J, et al. Stress-driven discovery of new angucycline-type antibiotics from a marine Streptomyces pratensis NA-ZhouS1. Marine Drugs. 2018;16(9):331. DOI: 10.3390/md16090331
  28. 28. Al Farraj DA, Varghese R, Vágvölgyi C, Elshikh MS, Alokda AM, Mahmoud AH. Antibiotics production in optimized culture condition using low cost substrates from Streptomyces sp. AS4 isolated from mangrove soil sediment. Journal of King Saud University-Science. 2020;32(2):1528-1535. DOI: 10.1016/j.jksus.2019.12.008
  29. 29. Williams DE, Dalisay DS, Chen J, Polishchuck EA, Patrick BO, Narula G, et al. Aminorifamycins and sporalactams produced in culture by a Micromonospora sp. isolated from a northeastern-pacific marine sediment are potent antibiotics. Organic Letters. 2017;19(4):766-769. DOI: 10.1021/acs.orglett.6b03619
  30. 30. Pérez-Bonilla M, Oves-Costales D, De la Cruz M, Kokkini M, Martín J, Vicente F, et al. Phocoenamicins B and C, new antibacterial spirotetronates isolated from a marine Micromonospora sp. Marine Drugs. 2018;16(3):95. DOI: 10.3390/md16030095
  31. 31. Auckloo BN, Pan C, Akhter N, Wu B, Wu X, He S. Stress-driven discovery of novel cryptic antibiotics from a marine fungus Penicillium sp. BB1122. Frontiers in Microbiology. 2017;8:1450. DOI: 10.3389/fmicb.2017.01450
  32. 32. Wu B, Wiese J, Wenzel-Storjohann A, Malien S, Schmaljohann R, Imhoff JF. Engyodontochones, antibiotic polyketides from the marine fungus Engyodontium album strain LF069. Chemistry–A European Journal. 2016;22(22):7452-7462. DOI: 10.1002/chem.201600430
  33. 33. Inostroza A, Lara L, Paz C, Perez A, Galleguillos F, Hernandez V, et al. Antibiotic activity of emerimicin IV isolated from Emericellopsis minima from Talcahuano Bay, Chile. Natural Product Research. 2018;32(11):1361-1364. DOI: 10.1080/14786419.2017.1344655
  34. 34. Rekadwad B, Khobragade C. Marine polyextremophiles and their biotechnological applications. In: Kalia VC, Kumar P, editors. Microbial Applications. Cham: Springer; 2017. pp. 319-331. DOI: 10.1007/978-3-319-52666-9_15
  35. 35. Trenozhnikova L, Azizan A. Discovery of actinomycetes from extreme environments with potential to produce novel antibiotics. Central Asian Journal of Global Health. 2018;7(1):337. DOI: 10.5195/cajgh.2018.337
  36. 36. Stierle AA, Stierle DB, Decato D, Priestley ND, Alverson JB, Hoody J, et al. The berkeleylactones, antibiotic macrolides from fungal coculture. Journal of Natural Products. 2017;80(4):1150-1160. DOI: 10.1021/acs.jnatprod.7b00133
  37. 37. Nathan C, Cunningham-Bussel A. Beyond oxidative stress: An immunologist’s guide to reactive oxygen species. Nature Reviews. Immunology. 2013;13(5):349-361. DOI: 10.1038/nri3423
  38. 38. Lushchak VI. Free radicals, reactive oxygen species, oxidative stress and its classification. Chemico-Biological Interactions. 2014;224:164-175. DOI: 10.1016/j.cbi.2014.10.016
  39. 39. Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Current Biology. 2014;24:R453-R462. DOI: 10.1016/j.cub.2014.03.034
  40. 40. Krumova K, Cosa G. Overview of reactive oxygen species. In: Nonell S, Flors C, editors. Singlet Oxygen: Applications in Bioscience and Nanoscience. EU: Royal Society of Chemistry; 2016. p. 3
  41. 41. Nimse SB, Pal D. Free radicals, natural antioxidants, and their reaction mechanisms. RSC Advances. 2015;5:27986-28006. DOI: 10.1039/C4RA13315C
  42. 42. Radi R. Oxygen radicals, nitric oxide, and peroxynitrite: Redox pathways in molecular medicine. PNAS. 2018;115(23):5839-5848. DOI: 10.1073/pnas.1804932115
  43. 43. Chehue Romero A, Olvera Hernández EG, Flores Cerón T, Álvarez-Chávez A. The exogenous antioxidants. In: Morales-González JA, editor. Oxidative Stress and Chronic Degenerative Diseases—A Role for Antioxidants. Croatia: InTechOpen; 2013. p. 33. DOI: 10.5772/52490
  44. 44. Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. International Journal of Biomedical Sciences. 2008;4(2):89-96
  45. 45. Phaniendra A, Jestadi DB, Periyasami L. Free radicals: Properties, sources, targets and their implications in various diseases. Indian Journal of Clinical Biochemistry. 2015;30(1):11-26. DOI: 10.1007/s12291-014-0446-0
  46. 46. Xu J, Leeuwenburgh C. Free radicals and oxidative stress: Basic concepts and misconceptions. In: Miller J, Le Prell CG, Rybak L, editors. Free Radicals in ENT Pathology. SWT: Humana Press; 2015. pp. 10-15
  47. 47. Gozari M, Bahador N, Jassbi AR, Mortazavi MS, Hamzehei S, Eftekhar E. Isolation, distribution and evaluation of cytotoxic and antioxidant activity of cultivable actinobacteria from the Oman Sea sediments. Acta Oceanologica Sinica. 2019;38(12):84-90. DOI: 10.1007/s13131-019-1515-2
  48. 48. Dholakiya RN, Kumar R, Mishra A, Mody KH, Jha B. Antibacterial and antioxidant activities of novel actinobacteria strain isolated from Gulf of Khambhat, Gujarat. Frontiers in Microbiology. 2017;8:2420. DOI: 10.3389/fmicb.2017.02420
  49. 49. Ser HL, Tan LTH, Palanisamy UD, Abd Malek SN, Yin WF, Chan KG, et al. Streptomyces antioxidans sp. nov., a novel mangrove soil actinobacterium with antioxidative and neuroprotective potentials. Frontiers in Microbiology. 2016;7:899. DOI: 10.3389/fmicb.2016.00899
  50. 50. Law JWF, Ser HL, Ab Mutalib NS, Saokaew S, Duangjai A, Khan TM, et al. Streptomyces monashensis sp. nov., a novel mangrove soil actinobacterium from East Malaysia with antioxidative potential. Scientific Reports-UK. 2019;9(1):1-18. DOI: 10.1038/s41598-019-39592-6
  51. 51. De Carvalho J, Cardoso L, Ghiggi V, Woiciechowski A, Vandenberghe L, Soccol C. Microbial pigments. In: Brar SK, Dhillon GS, Soccol CR, editors. Biotransformation of Waste Biomass into High Value Biochemicals. NY: Springer; 2014. pp. 73-97
  52. 52. Squillaci G, Parrella R, Carbone V, Minasi P, La Cara F, Morana A. Carotenoids from the extreme halophilic archaeon Haloterrigena turkmenica: Identification and antioxidant activity. Extremophiles. 2017;21:933-945. DOI: 10.1007/s00792-017-0954-y
  53. 53. Pereira Cipolatti E, Diaz Remedi R, dos Santos SC, Bueno Rodrigues A, Markowiski Gonçalves Ramos J, Veiga Burkert CA, et al. Use of agroindustrial byproducts as substrate for production of carotenoids with antioxidant potential by wild yeasts. Biocatalysis and Agricultural Biotechnology. 2019;20:101208. DOI: 10.1016/j.bcab.2019.101208
  54. 54. Young AJ, Lowe GL. Carotenoids-antioxidant properties. Antioxidants. 2018;7(2):28. DOI: 10.3390/antiox7020028
  55. 55. Elfeky N, Elmahmoudy M, Zhang Y, Guo J, Bao Y. Lipid and carotenoid production by Rhodotorula glutinis with a combined cultivation mode of nitrogen, sulfur, and aluminium stress. Applied Sciences. 2019;9(12):2444. DOI: 10.3390/app9122444
  56. 56. Massoud R, Khosravi-Darani K. A review on the impacts of process variables on microbial production of carotenoid pigments. In: Grumezescu AM, Holban AM, editors. Food Biosynthesis. UK: Academic Press; 2017. pp. 183-211. DOI: 10.1016/B978-0-12-811372-1.00006-3
  57. 57. Mayasari E, Raya I, Natsir H. Effect of Fe2+ and Mn2+ addition on growth and β-carotene production of Dunaliella salina. Journal of Physics: Conference Series. 2018;979(1):012012. DOI: 10.1088/1742-6596/979/1/012012
  58. 58. Ortega-Cabello L, Pérez-Méndez HI, Manjarrez-Alvarez N, Solís-Oba A, López-Luna A. Effect of iron salts on Rhodococcus sp. and Gordonia sp. on carotenoid production. Revista Mexicana de Ingeniería Química. 2017;16(1):1-10
  59. 59. Chatterjee T, Das A. Natural agents with iron chelation potential: A new hope and promise for cheaper supplement of costly iron chelating medicines for transfusion dependent thalassaemics. International Journal of Advanced Research. 2016;4(3):1258-1268
  60. 60. Ortega Cabello L, Pérez Méndez HI, Manjarrez Alvarez N, López-Luna A, Solís Oba A, Solís OM. Comparación de la actividad antioxidante de carotenoides en extractos crudos y pre-purificados de actinobacterias marinas. Revista Mexicana de Ciencias Farmaceuticas. 2016;47(2):60-65
  61. 61. Quesada S, Azofeifa G, Jatunov S, Jiménez G, Navarro L, Gómez G. Carotenoids composition, antioxidant activity and glycemic index of two varieties of Bactris gasipaes. Emirates Journal of Food and Agriculture. 2011;23(6):482-489
  62. 62. Wang CC, Ding S, Chiu KH, Liu WS, Lin TJ, Wen ZH. Extract from a mutant Rhodobacter sphaeroides as an enriched carotenoid source. Food & Nutrition Research. 2016;60(1):29580. DOI: 10.3402/fnr.v60.29580
  63. 63. Li Z, Kong L, Hui B, Shang X, Gao L, Luan N, et al. Identification and antioxidant activity of carotenoids from superfine powder of Rhodobacter sphaeroides. Emirates Journal of Food and Agriculture. 2017;29(11):833-845. DOI: 10.9755/ejfa.2017.v29.i11.1479
  64. 64. Raddatz-Mota D, Pérez-Flores LJ, Carrari F, Mendoza-Espinoza JA, de León-Sánchez FD, Pinzón-López LL, et al. Achiote (Bixa orellana L.): A natural source of pigment and vitamin E. Journal of Food Science and Technology. 2017;54(6):1729-1741. DOI: 10.1007/s13197-017-2579-7
  65. 65. Saini RK, Keum YS. Progress in microbial carotenoids production. Indian Journal of Microbiology. 2017;57(1):129-130. DOI: 10.1007/s12088-016-0637-x
  66. 66. Hecht F, Pessoa CF, Gentile LB, Rosenthal D, Carvalho DP, Fortunato RS. The role of oxidative stress on breast cancer development and therapy. Tumor Biology. 2016;37(4):4281-4291. DOI: 10.1007/s13277-016-4873-9
  67. 67. Auyeung KK, Ko JK. Angiogenesis and oxidative stress in metastatic tumor progression: Pathogenesis and novel therapeutic approach of colon cancer. Current Pharmaceutical Design. 2017;23(27):3952-3961. DOI: 10.2174/1381612823666170228124105
  68. 68. Ma-on C, Sanpavat A, Whongsiri P, Suwannasin S, Hirankarn N, Tangkijvanich P, et al. Oxidative stress indicated by elevated expression of Nrf2 and 8-OHdG promotes hepatocellular carcinoma progression. Medical Oncology. 2017;34(4):57. DOI: 10.1007/s12032-017-0914-5
  69. 69. Thyagarajan A, Sahu RP. Potential contributions of antioxidants to cancer therapy: Immunomodulation and radiosensitization. Integrative Cancer Therapies. 2018;17(2):210-216. DOI: 10.1177/1534735416681639
  70. 70. Ser HL, Palanisamy U, Yin W-F, Chan K-G, Goh BH, Lee LH. Streptomyces malaysiense sp. nov.: A novel malaysian mangrove soil actinobacterium with antioxidative activity and cytotoxic potential against human cancer cell lines. Scientific Reports-UK. 2016;6:24247. DOI: 10.1038/srep24247
  71. 71. Bauermeister A, Zucchi TD, Moraes LAB. Mass spectrometric approaches for the identification of anthracycline analogs produced by actinobacteria. Journal of Mass Spectrometry. 2016;51(6):437-445. DOI: 10.1002/jms.3772
  72. 72. Malla S, Niraula NP, Singh B, Liou K, Sohng JK. Limitations in doxorubicin production from Streptomyces peucetius. Microbiological Research. 2010;165(5):427-435. DOI: 10.1016/j.micres.2009.11.006
  73. 73. Busi S, Pattnaik SS. Current status and applications of actinobacteria in the production of anticancerous compounds. In: Singh BP, Gupta VK, Passari AK, editors. New and Future Developments in Microbial Biotechnology and Bioengineering. Vol. 2018. Netherlands: Elsevier; 2018. pp. 137-153
  74. 74. Davies-Bolorunduro OF, Adeleye IA, Akinleye MO, Wang PG. Anticancer potential of metabolic compounds from marine actinomycetes isolated from Lagos Lagoon sediment. Journal of Pharmaceutical Analysis. 2019;9(3):201-208. DOI: 10.1016/j.jpha.2019.03.004
  75. 75. Law JWF, Ser HL, Duangjai A, Saokaew S, Bukhari SI, Khan TM, et al. Streptomyces colonosanans sp. nov., a novel actinobacterium isolated from Malaysia mangrove soil exhibiting antioxidative activity and cytotoxic potential against human colon cancer cell lines. Frontiers in Microbiology. 2017;8:877. DOI: 10.3389/fmicb.2017.00877
  76. 76. Chen C, Ye Y, Wang R, Zhang Y, Wu C, Debnath SC, et al. Streptomyces nigra sp. nov. is a novel actinobacterium isolated from mangrove soil and exerts a potent antitumor activity in vitro. Frontiers in Microbiology. 2018;9:1587. DOI: 10.3389/fmicb.2018.01587
  77. 77. Zhang XG, Liu ZY, Liu JW, Zeng YL, Guo GJ, Sun QY. Antitumor activity of a Rhodococcus sp. Lut0910 isolated from polluted soil. Tumour Biology. 2017;39(6):1-9. DOI: 1010428317711661
  78. 78. Chen L, Huang G. Antitumor activity of polysaccharides: An overview. Current Drug Targets. 2018;19(1):89-96. DOI: 10.2174/1389450118666170704143018
  79. 79. Washington KE, Kularatne RN, Biewer MC, Stefan MC. Combination loading of doxorubicin and resveratrol in polymeric micelles for increased loading efficiency and efficacy. ACS Biomaterials Science & Engineering. 2018;4(3):997-1004. DOI: 10.1021/acsbiomaterials.7b00972
  80. 80. Gu J, Hu W, Zhang D-D. Resveratrol, a polyphenol phytoalexin, protects against doxorubicin-induced cardiotoxicity. Journal of Cellular and Molecular Medicine. 2015;19(10):2324-2328. DOI: 10.1111/jcmm.12633
  81. 81. Farag MMS, Moghannem SAM, Shehabeldine AM, Azab MS. Antitumor effect of exopolysaccharide produced by Bacillus mycoides. Microbial Pathogenesis. 2020;140:103947. DOI: 10.1016/j.micpath.2019.103947
  82. 82. Insulkar P, Kerkar S, Lele SS. Purification and structural-functional characterization of an exopolysaccharide from Bacillus licheniformis PASS26 with in-vitro antitumor and wound healing activities. International Journal of Biological Macromolecules. 2018;120:1441-1450. DOI: 10.1016/j.ijbiomac.2018.09.147
  83. 83. Sun N, Liu H, Liu S, Zhang X, Chen P, Li W, et al. Purification, preliminary structure and antitumor activity of exopolysaccharide produced by Streptococcus thermophilus CH9. Molecules. 2018;23(11):2898. DOI: 10.3390/molecules23112898
  84. 84. Li H, Yu H, Zhu H. Structure studies of the extracellular polysaccharide from Trichoderma sp. KK19L1 and its antitumor effect via cell cycle arrest and apoptosis. Applied Biochemistry and Biotechnology. 2017;182(1):128-141. DOI: 10.1007/s12010-016-2315-1
  85. 85. Chen L, Zhang QY, Jia M, Ming QL, Yue W, Rahman K, et al. Endophytic fungi with antitumor activities: Their occurrence and anticancer compounds. Critical Reviews in Microbiology. 2016;42(3):454-473. DOI: 10.3109/1040841X.2014.959892
  86. 86. Ran X, Zhang G, Li S, Wang J. Characterization and antitumor activity of camptothecin from endophytic fungus Fusarium solani isolated from Camptotheca acuminate. African Health Sciences. 2017;17(2):566-574. DOI: 10.4314/ahs.v17i2.34
  87. 87. Li Y, Guo S, Zhu H. Statistical optimization of culture medium for production of exopolysaccharide from endophytic fungus Bionectria ochroleuca and its antitumor effect in vitro. EXCLI Journal. 2016;15:211. DOI: 10.17179/excli2016-154
  88. 88. Smetanina OF, Yurchenko AN, Ivanets EV, Kalinovsky AI, Khudyakova YV, Dyshlovoy SA, et al. Unique prostate cancer-toxic polyketides from marine sediment-derived fungus Isaria felina. The Journal of Antibiotics. 2017;70(7):856-858. DOI: 10.1038/ja.2017.53
  89. 89. Singh S, Katoch A, Kaur R, Sran KS, Kumar B, Choudhury AR. Fermentative production and application of marine microbial exopolysaccharides. In: Trincone A, editor. Enzymatic Technologies for Marine Polysaccharides. USA: CRC Press; 2019. pp. 189-218
  90. 90. Decho AW, Gutierrez T. Microbial extracellular polymeric substances (EPSs) in ocean systems. Frontiers in Microbiology. 2017;8:922. DOI: 10.3389/fmicb.2017.00922
  91. 91. Caroff M, Karibian D. Structure of bacterial lipopolysaccharides. Carbohydrate Research. 2003;338(23):2431-2447. DOI: 10.1016/j.carres.2003.07.010
  92. 92. Bonev B. Lipopolysaccharide, structure and assembly of bacterial outer membranes. Biophysical Journal. 2018;114(3):270a
  93. 93. Domingues VS, Monteiro AS, Ferreira GF, Santos VL. Solid flocculation and emulsifying activities of the lipopolysaccharide produced by Trichosporon mycotoxinivorans CLA2. Applied Biochemistry and Biotechnology. 2017;182(1):367-381. DOI: 10.1007/s12010-016-2332-0
  94. 94. Liu Y, Wang KH, Chen HY, Li JR, Laurence TA, Ly S, et al. Periodic arrangement of lipopolysaccharides nanostructures accelerates and enhances the maturation processes of dendritic cells. ACS Applied Nano Materials. 2018;1(2):839-850. DOI: 10.1021/acsanm.7b00254
  95. 95. Masoud H. Novel adjuvants derived from attenuated lipopolysaccharides and lipid As of purple non-sulfur photosynthetic bacteria. Vaccine. 2019;37(26):3472-3477. DOI: 10.1016/j.vaccine.2019.04.097
  96. 96. Moradali MF, Rehm BH. Bacterial biopolymers: From pathogenesis to advanced materials. Nature Reviews. Microbiology. 2020;18:195-210. DOI: 10.1038/s41579-019-0313-3
  97. 97. Sahana TG, Rekha PD. A novel exopolysaccharide from marine bacterium Pantoea sp. YU16-S3 accelerates cutaneous wound healing through Wnt/β-catenin pathway. Carbohydrate Polymers. 2020;238:116191. DOI: 10.1016/j.carbpol.2020.116191
  98. 98. Ahmed Z, Ahmad A. Biopolymer produced by the lactic acid bacteria: Production and practical application. In: Holban AM, Mihai A, editors. Microbial Production of Food Ingredients and Additives. UK: Academic Press; 2017. pp. 217-257
  99. 99. Verma ML, Kumar S, Jeslin J, Dubey NK. Microbial production of biopolymers with potential biotechnological applications. In: Pal K, Banerjee I, Sarkar P, Kim D, Deng WP, Dubey NK, Majumder K, editors. Biopolymer-Based Formulations. Netherlands: Elsevier; 2020. pp. 105-137
  100. 100. Pantelić I, Lukić M, Gojgić-Cvijović G, Jakovljević D, Nikolić I, Lunter DJ, et al. Bacillus licheniformis Levan as a functional biopolymer in topical drug dosage forms: From basic colloidal considerations to actual pharmaceutical application. European Journal of Pharmaceutical Sciences. 2020;142:105109. DOI: 10.1016/j.ejps.2019.105109
  101. 101. Avsar G, Agirbasli D, Agirbasli MA, Gunduz O, Oner ET. Levan based fibrous scaffolds electrospun via co-axial and single-needle techniques for tissue engineering applications. Carbohydrate Polymers. 2018;193:316-325. DOI: 10.1016/j.carbpol.2018.03.075
  102. 102. Radhouani H, Gonçalves C, Maia FR, Oliveira JM, Reis RL. Biological performance of a promising Kefiran-biopolymer with potential in regenerative medicine applications: A comparative study with hyaluronic acid. Journal of Materials Science: Materials in Medicine. 2018;29(8):124. DOI: 10.1007/s10856-018-6132-7
  103. 103. Sun ML, Zhao F, Chen XL, Zhang XY, Zhang YZ, Song XY, et al. Promotion of wound healing and prevention of frostbite injury in rat skin by exopolysaccharide from the arctic marine bacterium Polaribacter sp. SM1127. Marine Drugs. 2020;18(1):48. DOI: 10.3390/md18010048
  104. 104. Ding P, Song W, Yang Z, Jian J. Influence of Zn(II) stress-induction on component variation and sorption performance of extracellular polymeric substances (EPS) from Bacillus vallismortis. Bioprocess and Biosystems Engineering. 2018;41(6):781-791. DOI: 10.1007/s00449-018-1911-6
  105. 105. Estevinho BN, Mota R, Leite JP, Tamagnini P, Gales L, Rocha F. Application of a cyanobacterial extracellular polymeric substance in the microencapsulation of vitamin B12. Powder Technology. 2019;343:644-651. DOI: 10.1016/j.powtec.2018.11.079
  106. 106. Leite JP, Mota R, Durão J, Neves SC, Barrias CC, Tamagnini P, et al. Cyanobacterium-derived extracellular carbohydrate polymer for the controlled delivery of functional proteins. Macromolecular Bioscience. 2017;17(2):1600206. DOI: 10.1002/mabi.201600206
  107. 107. Yahav S, Berkovich Z, Ostrov I, Reifen R, Shemesh M. Encapsulation of beneficial probiotic bacteria in extracellular matrix from biofilm-forming Bacillus subtilis. Artificial Cells, Nanomedicine and Biotechnology. 2018;46(2):974-982. DOI: 10.1080/21691401.2018.1476373
  108. 108. Pi S, Li A, Cui D, Su Z, Feng L, Ma F, et al. Biosorption behavior and mechanism of sulfonamide antibiotics in aqueous solution on extracellular polymeric substances extracted from Klebsiella sp. J1. Bioresource Technology. 2019;272:346-350. DOI: 10.1016/j.biortech.2018.10.054
  109. 109. Polesel F, Lehnberg K, Dott W, Trapp S, Thomas KV, Plósz BG. Factors influencing sorption of ciprofloxacin onto activated sludge: Experimental assessment and modelling implications. Chemosphere. 2015;119:105-111. DOI: 10.1016/j.chemosphere.2014.05.048
  110. 110. Gu C, Gao P, Yang F, An D, Munir M, Jia H, et al. Characterization of extracellular polymeric substances in biofilms under long-term exposure to ciprofloxacin antibiotic using fluorescence excitation-emission matrix and parallel factor analysis. Environemental Science and Pollution Research. 2017;24(15):13536-13545. DOI: 10.1007/s11356-017-8986-5
  111. 111. Zhang H, Jia Y, Khanal SK, Lu H, Fang H, Zhao Q. Understanding the role of extracellular polymeric substances on ciprofloxacin adsorption in aerobic sludge, anaerobic sludge, and sulfate-reducing bacteria sludge systems. Environmental Science & Technology. 2018;52(11):6476-6486. DOI: 10.1021/acs.est.8b00568
  112. 112. Singh BP, Rateb M, Rodriguez-Couto S, MDLTD P, Li WJ. Microbial secondary metabolites: Recent developments and technological challenges. Frontiers in Microbiology. 2019;10:914. DOI: 10.3389/fmicb.2019.00914
  113. 113. Baltz RH. Gifted microbes for genome mining and natural product discovery. Journal of Industrial Microbiology & Biotechnology. 2017;44(4-5):573-588. DOI: 10.1007/s10295-016-1815-x
  114. 114. Kang HS. Phylogeny-guided (meta) genome mining approach for the targeted discovery of new microbial natural products. Journal of Industrial Microbiology & Biotechnology. 2017;44(2):285-293. DOI: 10.1007/s10295-016-1874-z
  115. 115. Zhang MM, Wang Y, Ang EL, Zhao H. Engineering microbial hosts for production of bacterial natural products. Natural Product Reports. 2016;33(8):963-987. DOI: 10.1039/C6NP00017G
  116. 116. Nybo SE, Kharel MK. Recent developments in the quest for novel microbial natural products. In: Rahman A, editor. Studies in Natural Products Chemistry. USA: Elsevier; 2018. pp. 109-152
  117. 117. Tomm HA, Ucciferri L, Ross AC. Advances in microbial culturing conditions to activate silent biosynthetic gene clusters for novel metabolite production. Journal of Industrial Microbiology & Biotechnology. 2019;46(9-10):1381-1400. DOI: 10.1007/s10295-019-02198-y
  118. 118. Pagliaro M. Green and economically viable extraction of natural products: From lab to marketplace. Chimica Oggi. 2017;35(3):71-72
  119. 119. Abas F, Intan SI, Nordin HL. Generalized likelihood uncertainty estimation (GLUE) methodology for optimization of extraction in natural products. Food Chemistry. 2018;250:37-45. DOI: 10.1016/j.foodchem.2018.01.023
  120. 120. Zhang Q-W, Li-Gen L, Wen-Cai Y. Techniques for extraction and isolation of natural products: A comprehensive review. Chinese Medicine-UK. 2018;13(1):20. DOI: 10.1186/s13020-018-0177-x
  121. 121. Ahmad I. Ionic liquid-based microwave-assisted extraction: Fast and green extraction method of secondary metabolites on medicinal plant. Pharmacognosy Reviews. 2018;12(23):20-26
  122. 122. Li Y, Fabiano-Tixier AS, Chemat F. Vegetable oils as alternative solvents for green extraction of natural products. In: Chemat S, editor. Edible Oils: Extraction, Processing and Applications. United States: CRC Press; 2017. p. 25
  123. 123. Herrero M, Ibañez E. Green extraction processes, biorefineries and sustainability: Recovery of high added-value products from natural sources. The Journal of Supercritical Fluids. 2018;134:252-259. DOI: 10.1016/j.supflu.2017.12.002

Written By

Lucía Ortega Cabello

Submitted: 24 March 2020 Reviewed: 29 April 2020 Published: 27 May 2020