Bioprocess and Biosystems Engineering (2022) 45:1–12

https://doi.org/10.1007/s00449-021-02621-8

CRITICAL REVIEW

Microbial pigments as an alternative to synthetic dyes and food

additives: a brief review of recent studies
Masoud Aman Mohammadi1 · Hossein Ahangari2 · Saeed Mousazadeh2 · Seyede Marzieh Hosseini1 ·
Laurent Dufossé3

Received: 19 April 2021 / Accepted: 4 August 2021 / Published online: 9 August 2021
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021, corrected publication 2021

Abstract
Synthetic coloring agents have been broadly utilized in several industries such as food, pharmaceuticals, cosmetic and textile.
Recent surveys on the potential of teratogenicity and carcinogenicity of synthetic dyes have expressed concerns regarding
their use in foods. Worldwide, food industries have need for safe, natural and new colorings to add variety to foods and make
them appealing to consumers. Natural colorings not only expand the marketability of the food product, but also add further
healthful features such as antibacterial, antioxidant, anticancer and antiviral properties. Novel microbial strains should be
explored to meet the increasing global search of natural pigments and suitable techniques must be developed for the mar-
ketable production of new pigments, using microbial cultures, viz., fungi, and bacteria. To address the issue of the natural
coloring agents, this review presents the recent trends in several studies of microbial pigments, their biological properties
and industrial applications.

Keywords Pigments · Microbial · Antioxidant · Colorant · Dye · Anticancer

Introduction industries, while the remaining part was in food/feed and

pharmacy applications [3]. Moreover, as mentioned by Venil
About 3000 components in the food additive database of the et al. [4], textile industry, which utilizes huge amounts of
Food and Drug Administration (FDA) have been listed and chemical dyes, needs more quantities of biopigments and
recent studies testify that at present there are almost 2500 this issue has led to industrializing the production of eco-
kinds of food additives generally utilized in food products friendly and safe microbial colorants. Concerns about the
[1]. The current global use of pigments is nearly 9.7 million quality and safety of industrialized food products, which
tons [2]. In 2014, approximately 45% of the overall pig- contain artificial colorings, are the main reason for the sci-
ment application was associated with the paint and textile entist's attention toward non‐toxic and naturally derived
pigment alternatives [5, 6]. The significance of synthetic
* Seyede Marzieh Hosseini colorants is because the appearance of food products affects
[email protected] consumer’s preference. Thus, the necessity of artificial pig-
* Laurent Dufossé ments cannot be overseen if the customer’s tendency is to
[email protected] be satisfied [6, 7].
Microbial pigments are quickly replacing synthetic col-
1
Student Research Committee, Department of Food Science orings (some of them may have teratogenic and carcino-
and Technology, National Nutrition and Food Technology
Research Institute, Faculty of Nutrition Sciences, Food genic properties), since they are eco-friendly and nontoxic
Science and Technology, Shahid Beheshti University to humans for application as food additives [2, 8]. This trend
of Medical Sciences, Tehran, Iran is not only limited to microbial pigments as coloring agents.
2
Department of Food Science and Technology, Faculty For instance, microbial pigments with antioxidant activities,
of Nutrition and Food Sciences, Tabriz University of Medical such as saproxanthin and zeaxanthin, are preferred to syn-
Sciences, Tabriz, Iran thetic antioxidants like butylated hydroxyl acids (BHA) and
3
CHEMBIOPRO Lab, Ecole Supérieure d’Ingénieurs butylated hydroxyl toluene (BHT) [9]. In addition, microbial
Réunion Océan Indien (ESIROI), Université de La Réunion, pigments not only increase the color of foods, but also offer
Département Agroalimentaire, 97744 Saint‑Denis, France

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2 Bioprocess and Biosystems Engineering (2022) 45:1–12

populous medicinal advantages such as anticancer, antioxi- pigments provide other advantages such as low-cost produc-
dant, antimicrobial, immunosuppressive, anti-inflammatory, tion method, higher yield and economic extraction systems.
and antiproliferative activities [10–12]. Figure 1 illustrates Besides, the production of microbial pigments can be more
some of the biopigments that are generally recognized as improved by the optimization of growth conditions [23]. Dif-
safe (GRAS) and produced by microbial strains. ferent parameters are effective in optimization of microbial
Biopigments are produced by the various kinds of micro- pigment production, such as the type of nitrogen and carbon
organisms such as Serratia, Streptomyces, Monascus, Peni- source (nutrient medium composition), bioreactor type and
cillium mallochii, Paecilomyces, and Cordyceps [13–19]. culture conditions (aeration, agitation, temperature and pH).
Biopigments are being scrutinized particularly as a free Thus, several recent investigations have focused on studying
available source of coloring agents to substitute synthetic these parameters to achieve the proper growth requirements
chemical pigments. Moreover, the developing market of the of the pigment-producing microorganisms [24].
natural food colorings for maintaining consumer's interest Former investigations revealed that industrial production
depends on biopigments’ enhancement [19, 20]. A variety of microbial pigments continues to be in the exploration and
of biopigments are present in global trade, while the most developmental stage. This literature review explains the cur-
traditional ones include fungal Monascus pigments, asta- rent situation of microbial pigments as food colorings/addi-
xanthin (from Paracoccus carotinifaciens), Arpink red™ tives and emphasizes the significance of the novel pigment
(from Penicillium oxalicum), riboflavin (from fungus Ashbya secreting microbial strains, studying health-aiding effects,
gossypii), lycopene and β-carotene (from Blakeslea trispora industrial-scale production and exploring the systems with
and Dunaliella salina) and microalgal phytocyanin (from high-yield extraction.
Arthrospira platensis) [21]. Recent studies on biopigment
production by different microbial species and cultural condi-
tions are mentioned in Table 1.
By this time, the arguments against the application of Biosynthesis of microbial pigments
artificial coloring agents in many countries have prohibited
the consumption of several synthetic colorants such as Blue To upscale the production of biopigments, there is a neces-
FCF, Blue No.1 and No.2. Alternatively, at the present time, sity for the advancement of low-priced procedures for the
natural pigments are going to be more utilized rather than extraction of microbial pigments [25]. Studying biomecha-
chemically synthesized ones [22]. Industrial-scale produc- nisms involved in the creation of pigmented molecules is a
tion of biopigments is the other notable point. The microbial key factor in the optimization of industrial-scale production.

Fig. 1  Chemical structures of pharmacologically active microbial pigments

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Bioprocess and Biosystems Engineering (2022) 45:1–12 3

Table 1  Some of the recent studies on biopigment production by different microbial species on various carbon and nitrogen substrates
Microorganism Biopigment Culture condition Carbon/nitrogen source Pigment yield References

Monascus san- Monascus red Solid-state fermentation Broken rice 143.3 ODU/gds [66]
guineus NFCCI 2453
Rhodotorula mucilagi- β-Carotene Cultivation in synthetic YPG broth/agar, Luria– 118.3 µg/g [67]
nosa AJB01 media Bertani medium
Enterobacter sp. PWN1 Prodigiosin Submerged fermentation R-2A broth (casein acid 8.7 mg/g [68]
hydrolysate and yeast
extract)
Aspergillus carbonarius Melanin Solid and submerged Black carrot, apple, red 61.84 AU/g [69]
fermentation beet and pomegranate
pulps
Talaromyces purpureoge- Delphinidin Submerged fermentation Potato dextrose broth 0.6 to 138.3 U/ml [59]
nus KKP
Monascus pur- Monascus red Solid and submerged Sesame and olive oil, 12.8 AU/g [70]
pureus NRRL 1992 fermentation corn starch, yeast
extract
Fusarium Fusarubin and dihydro- Submerged fermentation POL medium (contain- 3.12 to 150.78 μg/mL [71]
solani BRM054066 fusarubin ing yeast extract and
glucose)
Monascus Monascus red Submerged fermentation Rice isolate and peptone 1.14 to 1.4 AU/g [72]
ruber OMNRC45
Talaromyces albobiverti- Orange and red pigment Submerged fermentation Potato dextrose broth 1.76 g/L orange, [73]
cillius 30,548 1.92 g/L red
Monascus pur- Monascus red Submerged fermentation Soy bean meal, yeast 4.54 AU/mL [74]
pureus ATCC 16,362 extract

Figure 2 shows a schematic diagram of the extraction and transitions. Nonetheless, until now it is not accepted that
purification procedure of microbial pigments. the enzymatic or biological pathways are similar or distinct
As mentioned by Nawaz et al. [22], several studies have for different pigment-producing microbes [22]. Due to the
suggested various biological pathways of pigment pro- high cost of synthetic growth media, the utilization of agro-
duction by microbial strains and biochemical enzymatic industrial wastes would be the solution for reducing the cost

Fig. 2  A demonstration of

laboratory-scale production of
microbial pigments

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4 Bioprocess and Biosystems Engineering (2022) 45:1–12

[26]. Some general techniques that are used in color extrac- for industrial-scale production. Therefore, these strains
tion from culture media include sonication-assisted extrac- should be manipulated for enhancement of pigment
tion, high hydrostatic pressure extraction (HHP), enzymatic generation capacity. Strain improvement is supposed to
extraction, pulse electric field extraction (PEF), gamma genetic mutation and/or other metabolic engineering tools
irradiation-assisted extraction and membrane technology to reform microbe characteristics to preferred biochemical
[27]. Herein, we have described a number of common bio- pathways that are responsible for the increase of biopig-
synthesis techniques. ment synthesis [31]. Recent studies indicated that use of
mutagens such as ethyl methane sulfonate (EMS), ultra-
Fermentation violet (UV), 1-methyl-3- nitro-1-nitrosoguanidine (NTG)
and microwaves can lead to several fold improvement of
As mentioned by Pombeiro-Sponchiado et al. [28], the fac- pigment generation [32]. For this purpose, the genetic
tors affecting pigment production in fermentation technology material of the microorganisms could be reorganized by
are nitrogen and carbon concentration, presence of oxygen, genetic engineering, which includes genetic mutations
medium pH, light, and the components of culture medium. and/or recombinant DNA technology. In this technology,
In this regard, Liu et al. [29] studied the application of rice the genetic structure of a microorganism changes in a
straw hydrolysate as a substrate in submerged fermentation mode to amplify the yield of pigments [33].
for the production of Monascus pigments (MPs) by Monas- By this way, Liu et al. [34] explored biotechnologi-
cus purpureus M630. MPs are secondary metabolites gener- cally produced Monascus azaphilone pigments (Mon-
ated by the fungal strains of Monascus spp., which are a part AzPs), which were generated by an engineered M. pur-
of important coloring agents in food, textile, and cosmetic pureus HJ11. Exogenous cyclic adenosine monophosphate
industries. The results indicated that M. purpureus M630 (cAMP) treatment intensified the MonAzPs production
makes 8.61 U ­mL−1 and 20.86 U ­mL−1 of extracellular MPs and increased the expression of cAMP phosphodiesterase
in rice straw hydrolysate alone or in combination with glu- gene, known as mrPDE, in M. purpureus HJ11. The results
cose fermentation medium, respectively. Further analysis indicated that ΔmrPDE strain generated MonAzPs at 8563
revealed that metabolites produced during the hydrolysis U ­g−1, with a 2.3-fold growth in comparison with the pri-
of rice straw (including furfural and 5′-hydroxymethyl fur- mary strain. Besides, the biochemical characteristics of
fural) has inhibitory effect on microbial growth and fermen- the engineered strain showed that NAPDH/NADP+ ratio
tation, while the M. purpureus M630 improves adaptation of the ΔmrPDE strain was noticeably higher than that of
mechanisms in response to these metabolites. This study the wild strain, which led to a higher percentage of Mon-
validates that submerged fermentation of rice straw hydro- AzPs. In addition, it should be noted that, through fed-
lysate by Monascus spp. can provide a low-cost method for batch fermentation of the ΔmrPDE strain, the final yield of
the production of the MPs [29]. yellow MonAzPs achieved 8739 U.g−1. This study presents
In another study, Loh et al. [30] investigated the ability a roadmap for genetic engineering surveys headed for the
of Gordonia terrae TWRH01, a marine bacterium isolated production of biopigments by other fungal strains [34].
from seawater of northern Taiwan, in the production of Recently, Song et al. [35] conducted a study on explor-
carotenoids. The biochemical characteristics of the G. ter- ing the gene engineering of a Chlamydomonas strain for
rae TWRH01 were analyzed by application of different zeaxanthin production. Zeaxanthin is a type of biopig-
fermentation strategies. According to the results, G. ter- ment that assists the body in avoiding age-related macular
rae TWRH01 can professionally produce carotenoids in cul- degeneration. In this study, a double knockout mutant was
tures adjusted to pH 7 and containing 16 g ­L−1 yeast extract created by the CRISPR-Cas9 ribonucleoprotein-mediated
as the nitrogen source and 16 g ­L−1 sucrose as the carbon knock-in system and then lycopene epsilon cyclase (LCYE)
source. Moreover, the optimization of fermentation process was modified for the removal of the α-branch of xantho-
yielded 10.58 μmol ­L−1 relative β-carotene concentration phyll biosynthesis in a knockout mutant of the zeaxanthin
and 15.29 g.L−1 dry biomass; however GC–MS analysis epoxidase gene (ZEP). Results signified that, after 3 days
showed that the produced pigments were echinenone and of cultivation, the double knockout mutant had zeaxanthin
adonixanthin 3′-β-d-glucoside, which are the main carot- yield 5.24 mg ­L−1 and zeaxanthin content 7.28 mg ­g−1,
enoid derivatives. This novel bacterial strain can serve as which was about 60% higher than that of parental cell
a bioresource of the commercial natural carotenoids [30]. lines. This work indicated that the difficulties of the down-
stream process for the fabrication of high-purity zeaxan-
Genetic engineering thin can be solved by genetic engineering [35].

Wild strains of pigment-secreting microbes generate

low quantities of the biopigments, which cannot be used

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Bioprocess and Biosystems Engineering (2022) 45:1–12 5

Agro‑industrial waste juice as a substitute of fermentation culture medium. Yeast

extract, pH, sugarcane juice and stirring speed were explored
The accumulation of food waste can lead to significant as the independent variables affecting yeast cell growth and
global concerns such as economic, environmental and social pigment production. The results showed that the maxi-
issues. On the other hand, these by-products are a highly mum production of carotenoid was 1300 μg L ­ −1 which was
−1
valued source of important antioxidant compounds such as obtained in 6 g L ­ yeast extract, initial pH of 6.8, 40%
polyphenols that should be extracted for industrial applica- sugarcane juice, and stirring speed of 176 RPM. This study
tions through biotechnological approaches. Therefore, the revealed that controlling the environmental conditions
management of industrial food by products is necessary for (including pH and stirring speed) in sugarcane culture sup-
the removal of accumulated food waste, and to reprocess plemented with yeast extract could advance the bioproduc-
these rich by-products to increase the economic value [36]. tion of carotenoids and biomass [42].
According to Kalra et al. [18], Nevzglyadova et al. [37]
and Fernandes et al. [38], filamentous fungi and yeasts are a
valuable source of numerous pigments such as phenazines, Industrial applications and pharmacological
melanins, quinones, and flavins. The yeast groups that can activities
synthesize carotenoid pigments include species of the gen-
era Rhodotorula, Rhodosporidium, Sporidiobolus, Sporobo- Legislation of biopigments
lomyces and Phaffia rhodozyma (also its teleomorph Xan-
thophyllomyces dendrorhous) [39]. A new pigment being Similar to all confirmed food additives, the microbial pig-
studied is the red pigment generated by Saccharomyces ments are subject to accurate regulation and approval pro-
cerevisiae mutants, which is a result of polymerization of cedure before the application in food industry. In addition,
1-(5′-phosphoribosyl)-5-aminoimidazole containing amino biopigment purification technique must not let the entrance
acid residues and is characterized by a molecular weight of any allergic and/or toxic metabolite into the main prod-
from 2 to 10 kDa [40]. The biosynthesis of pigment in fungal uct [43]. A number of synthetic food colorants legislated
cells initiates with the conversion of acetyl-CoA, which is by FDA include mono- and di-azo dyes that are the most
created in the β-oxidation of fatty acids. In mevalonic acid general food-grade colorings, quinophthalones, xanthene
pathway, different biochemical reactions are catalyzed by dyes, and triarylmethane derivatives [44]. Mineral pig-
specific decarboxylases, kinases, and reductases to generate ments such as titanium dioxide (E171), iron oxides (E172)
isopentenyl pyrophosphate (IPP) that is a 5-carbon carot- and calcium carbonate (E170) [43] are also approved as food
enoid precursor and the addition reactions of three IPPs lead colorants. As mentioned by Nigam et al. [45], 43 colorings
to the formation of geranyl–geranyl pyrophosphate (GGPP), are accepted as food additives in European Union, while
with 20 carbon atoms per molecule. Finally, the compression around 30 colorants are permitted in the USA and 6 color-
of the two GGPP produces phytoene (C40) which is a pre- ings of these 30 additives are of microbial pigments which
cursor to biosynthesis of lycopene. Next, the produced lyco- are listed in Table 2.
pene can be transformed into lutein, γ-carotene, β-carotene,
torulene, torularhodin, astaxanthin, and zeaxanthin depend- Pigment purification
ing on the type of microorganisms [41].
In this context, Lobo et al. [42] studied the carotenoid Cost-effective separation techniques are significant factors
fabrication by pigmented yeasts Rhodotorula mucilaginosa, for industrial production of microbial pigments because
isolated from Bahia’s semi-arid region, employing sugarcane commercial recovery of biopigments with conventional

Table 2  List of commercially extracted food-grade colorings from microbes authorized by FDA, adapted from Caro, et al. [75] (https://​rdcu.​be/​
conAJ)
E Number* Color/shade Chemical Category Microbial source

E101 (iii) Yellow Flavin Riboflavin (from Bacillus subtilis), Other sources: Ashbya gossypii, Candida guillier-
mondii, Clostridium acetobutylicum and Debaryomyces subglobosus
E160a (ii) Orange- yellow Carotenoid β-Carotene (from Blakeslea trispora)
E160a (iv) Orange- yellow Carotenoid β-carotene (from Dunaliella salina), Other sources: Dunaliella bardawil
E160d (iii) Yellow to red Carotenoid Lycopene (from Blakeslea trispora)
E161j Yellow to red Carotenoid Astaxanthin (from Haematococcus pluvialis), other sources: Haematococcus lacustris,
Xanthophyllomyces dendrorhous
E161g Orange, red Carotenoid Canthaxanthin (from Haematococcus lacustris), other sources: Bradyrhizobium sp.

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6 Bioprocess and Biosystems Engineering (2022) 45:1–12

procedures is highly priced. Purification of microbial pig- 462 Da and solubility in organic solvents. For TDTA purifi-
ments can be carried out by conventional techniques such as cation, 10 L of the fermentation broth was concentrated by
differential extraction, countercurrent extraction, differential evaporation to a volume of 1 L. The concentrate was eight
crystallization and adsorption column chromatography [32]. times extracted with ethyl acetate (EtOAc) and the final
Moreover, extraction of pigments by organic solvents is a combined extracts were evaporated to 150 ml under reduced
time-consuming and problematic method due to the consid- pressure. Then the remaining extract was passed over a silica
erable quantities of exhausted solvents and even low purity gel column and the concentrated fractions were monitored
of the final product. The most generally used solvents are by thin layer chromatography (TLC). Finally, the pure blue
chloroform, hexane, acetone, cyclohexane, dichloromethane, TDTA pigment powder from HPLC purification was gained
methanol, isopropanol, ethanol, benzene, diethyl ether, car- for further identification. The color of TDTA was relatively
bon disulfide, and supercritical carbon dioxide, which have stable from pH 3 to pH 11, between 20 and 100 °C, and
been diffused in latest investigations [46]. On the other hand, under UV light. TDTA exhibited excellent free radical scav-
as most of the organic solvents are not natural, the utilizing enging properties, I­ C50 13.75 µg/mL and 41.04 µg/mL using
of solvents other than ethanol and water can cause failure 2,2-n-(3, 2-ethyl-benzothiazole-6-sulfonic acid) ammonium
to the aim of obtaining a microbial pigment for monitoring salt (ABTS) and 2, 20-diphenyl-1-picrylhydrazyl (DPPH),
purposes. Also, the use of non-ionic adsorption resins for an respectively. TDTA might be a promising source of bioactive
effective purification has been employed to many biomole- compound used as food additive [48].
cules such as organic acids, nucleic acids, and peptides [47].
These resins have an excessive loading capacity, and thus Industrial applications
can be useful in recovering biopigments in large scales, and
they can directly be utilized to adsorb different substances Food colorants
from the culture broth. The cost of purification is lowered
in this technique by decreasing the exhausted solvents and As synthetic color additives have exhibited negative health
increasing its reusability [32]. effects following their consumption, the food manufac-
In this regard, Zhu et al. [48] separated a novel blue pig- turers are turning to natural food colorants and this need
ment from Streptomyces sp. A1013Y. The purified natural should be met by the industrial production of biopig-
pigment was recognized as 4,8,13-trihydroxy-6,11-dione- ments [49]. Food and pharmacological products contain-
trihydrogranaticins A (TDTA) with a molecular weight of ing microbial pigments are presented in Fig. 3. Among

Fig. 3  A schematic of microbial pigment applications in food and cosmetics

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Bioprocess and Biosystems Engineering (2022) 45:1–12 7

different sources of natural colorings, microbial pigments Cosmetics

act as important food colorings due to the easy generation
and downstream procedure. Microbial fermentation is the The cosmetic industry has a vast global market and approxi-
most employed technique in pigment production, since it mately 2000 cosmetic manufacturers are present just inside
offers numerous advantages such as greater yield, inexpen- the USA [54]. Due to the application of different colorings
sive production, uncomplicated strain improvement, easier in cosmetics and its worldwide market, efforts have focused
extraction, and no seasonal changes [50]. According to on investigating the application of biopigments in cosmetics,
Dufossé [51], the success of an industrially produced pig- especially skincare products [54]. In this regard, Srinivasan
ment by fermentation or other techniques depends on its et al. [55] have reported the utilization of natural melanin
approval by national regulatory agencies like FDA/WHO, pigment extracted from Streptomyces bellus MSA1 in the
acceptability in the market and the initial investment for production of a bio lip ointment with the combination of
bringing the product to market. On the other hand, techni- lanolin, coconut oil and beeswax. Recent studies suggested
cal limitations are the main barrier for the industrial utili- the use of melanin pigment as an important element of sev-
zation of the source ingredients. eral sunscreens, beauty care products, plastic films and var-
In contrast, some pigments such as pyocyanins are not of nishes, since melanin pigments can disperse above 99% of
food grade, while they exhibit antioxidant and antimicrobial absorbed UV light [56].
activity. Pyocyanin is a blue-colored pigment that is found In a recent investigation, Choksi et al. [57] have studied
in Pseudomonas sp. In this regard, Saleem et al. [52] have 19 pigment-producing bacterial strains, which were isolated
characterized pyocyanin extracted from chromogenic Pseu- from water and soil samples in India. Pigments produced by
domonas species for its antioxidant potential. They studied the 17 isolates presented sunscreen activity at a concentra-
Pseudomonas aeruginosa DSM 50,071, which was isolated tion 0.4–8.34 µg.mL−1 and six of them exhibited prominent
from aquatic environments of Pakistan and identified by antibacterial activity. However, the biopigments produced
16S rRNA gene sequencing for production of pyocyanin. by Staphylococcus xylosus, which has been recognized by
P. aeruginosa is a Gram-negative, facultative, aerobic, rod- the 16S rRNA gene-sequencing method, were reported to be
shaped and opportunistic bacterium that produce different stable for up to five transfers and showed the most antibacte-
redox-active phenazine pigments including pyocyanin. The rial and antioxidant activity with sun-protecting activity that
results indicated that pyocyanin at concentration of 50 μg could be used as an important ingredient in cosmeceuticals
­ml−1 has 52.5% free radical scavenging of ABTS compared [57].
to BHA (86.0%) and Trolox (67.4%) and 58.0% inhibition of
DPPH in comparison to BHT (88.1%) and Trolox (68.5%). Pharmacological activities
Additionally, the pyocyanin at concentration of 50 μg m ­ l−1
exhibited antibacterial and antifungal activity against food- Microbial pigments are appreciated for a variety of pharma-
borne pathogens such as Staphylococcus aureus, Staphylo- cologically and biologically active compounds that exhibit
coccus enterica, Escherichia coli, Fusarium oxysporum and anticancer, antibiotic, antioxidant, immunosuppressive and
Aspergillus niger [52]. antiproliferative properties; thus, they can be a dominant
In another survey conducted by Ramesh et al. [53], the substitute for synthetic constituents in the development of
diversity and bioprospecting aspects of pigments extracted new drugs for treatment of pathological disorders. Efforts for
from marine bacterial strains were studied. Approximately, investigating the biopigments produced by microbial strains
180 samples were collected and the results revealed that are quickly growing as well as the number of isolated com-
orange- and red-pigmented bacterial stains were most pounds in comparison to previous sources [58]. A number
abundant populations; from these strains 14 isolates were of recent studies on biopigments and their pharmacological
selected due to their intense pigmentation, and the pigments functions are listed in Table 3.
were tested for food colorant applications and bioactive
nature. Two red-pigmented strains (BSE6.1 and S2.1) pre- Antioxidant activity
sented antioxidant potential, antibacterial activity and food
colorant properties, and the chemical analysis (by HPLC, Recently, Keekan et al. [59] have studied the production
TLC and GC–MS) pointed out that prodigiosin was the of red pigment and its antioxidant activity by Talaromyces
main chemical component of pigments. Antibacterial tests purpureogenus KKP isolated from soil. The central com-
proved that BSE6.1 requires 400 µg and S2.1 needs 300 µg posite design (CCD) was used for optimization of cultural
and 150 µg of the red pigment for complete inhibition of S. parameters including temperature, pH, peptone and dextrose
aureus subsp. aureus. According to 16S rRNA sequence concentrations. The results revealed that 6-hydroxymethyl-7,
analysis, the strains BSE6.1 and S2.1 were identified as delphinidin, 8-dihydropterin, limonene, D-mannose-6-phos-
Streptomyces sp. and Zooshikella sp., respectively [53]. phate and CDP-DG (18:0/18:0) were the main elements of

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8 Bioprocess and Biosystems Engineering (2022) 45:1–12

Table 3  Biopigments from microbial species and their pharmacological applications

Biopigment Microbial species Carbon/nitrogen source Activity Reference

Violacein Chromobacterium violaceum Liquid pineapple waste medium Antibacterial [76]

UTM5
9(10H)-Acridanone Streptomyces fradiae strain Tryptone yeast extract medium Antiviral against white spot syn- [77]
VITMK2 (ISP-1) drome virus (WSSV)
Staphyloxanthin Staphylococcus galli- Milk salt agar medium, nutrient Antioxidant, anticancer, antibacte- [78]
narum KX912244 broth rial against E. coli, S. aureus
Prodigiosin Serratia marcescens Nutrient broth, lysogency broth Anticancer, antioxidant [79]
(Lb)
β-carotene, torular- Rhodotorula mucilaginosa MTCC- Potato skin, mung bean husk, onion Anticancer, antioxidant [80]
hodin, torulene 1403 peels and pea pods
Astaxanthin Xanthophyllomyces dendrorhous Yeast and Mold broth (YM) Powerful antioxidant, anticancer [81]
β-carotene Planococcus sp. TRC1 Sugarcane bagasse and paper mill Antibiotic and antioxidant [82]
sludge
Violacein Chromobacterium violaceum Luria–Bertani broth Nephroprotective property, anti- [83]
oxidant
Yellow carotenoids Kocuria flava SIF3 Nutrient broth Antioxidant and antimicrobial [84]
Pyocyanin Pseudomonas aeruginosa Nutrient agar, MacConkey agar Cytotoxic for MG-63 osteosarcoma [85]
cell lines, antioxidant

the produced pigments. The radical scavenging capacity of In another study, Alem et al. [62] investigated the pro-
the extracted red pigment was determined through DPPH duction and health benefits of the purple pigment, which is
and ABTS assays. The DPPH scavenging rate ranged from known as violacein and is secreted by an Antarctic bacte-
10 to 90% with half inhibition concentration ­(IC50) value rial isolate. Many studies have reported the antiprolifera-
of 40 µg ­mL −1 and the standard ascorbic acid showed tive activity of violacein in many cell lines. The results of
­IC50 value of 7.25 µg ­mL−1. In ABTS test, the ­IC50 of red survival assays revealed that the natural violacein has anti-
pigment was 35 µg m­ L−1, while ascorbic acid was 7 µg m
­ L−1 proliferative activity and sensitized cervix carcinoma cells
[59]. (HeLa) to cisplatin. In addition, micronucleus assays showed
violacein has no genotoxic activity in HeLa cells. This study
Anticancer and antiproliferative activity confirmed that violacein is a robust biopigment which exhib-
its antiproliferative and/or anticancer activity for treatment
Zeng et al. [60] explored the antioxidant and anticancer of cervical cancer [62].
capacity of raw and fermented coix seed, by M. purpureus,
using free radical scavenging assays and human laryngeal Antifungal activity
carcinoma cell HEp2, respectively. After fermentation,
the coixenolide, tocols, and γ-oryzanol contents increased In this regard, Dawoud et al. [63] have conducted a
approximately 2, 4, and 25 times, respectively, compared to study on the antifungal and antibacterial activity of yel-
the raw seed. The extracted pigment produced by M. pur- low pigment produced by 20 different strains of endoli-
pureus exhibited higher antioxidant activity in scavenging chenic Bacillus sp. isolated from the lichen Dirinaria
free radicals and inhibiting lipid oxidation. The antican- aegialita. The highest pigment yield was obtained in
cer activity of the extract was assessed by using the HEp2 Luria–Bertani medium by a strain that was recognized
cell line of human laryngeal carcinoma which accounts for as Bacillus gibsonii based on 16S rRNA genome sequence
25% of head and neck cancers [61]. The ­IC50 of lipophilic with 99% similarity. Based on ABTS assay, the ­SC50 of the
extract from fermented seeds for inhibiting HEp2 cell lines pigment has been reported to be 75.125 ± 0.18 µg m ­ L−1.
decreased about 42%. This study revealed that fermentation Simultaneously, the antifungal activity of the pigment was
by pigment-producing M. purpureus improved the antican- assessed against different fungal species, viz., Fusarium
cer activity of the extract, while its cytotoxicity against the oxysporum, Rhodotorula solani and Sterptomyces rolfsi.
normal CV-1 cells was low at the concentration of 10 mg Moreover, terbinafine hydrochloride (1 mg m ­ L −1) and
­mL−1, just 30.5% of the cells were inhibited. This study methanol (100 µL) were exploited as positive and nega-
established that fermentation of coix seeds by M. purpureus tive controls, respectively. The results of antifungal test
could improve the anticancer activity [60]. pointed out that this pigment inhibits R. solani and S.

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Bioprocess and Biosystems Engineering (2022) 45:1–12 9

rolfsi; however, mycelia lysis and length reduction were Conclusion and future perspectives
reported. On the contrary, no antibacterial activity has
been reported [63]. Positive public opinion regarding natural colors is being
encouraged due to the safety and their nontoxic and eco-
friendly nature, even with the prevalence of synthetic col-
Antibacterial activity orants. Recent researches have revealed that the produc-
tion of biopigments is an economical approach to extract
Pachaiyappan et al. [64] investigated the biological charac- these beneficial metabolites; however, some limitations
teristics of carotenoids extracted from marine endophytic still exist including low stability, high cost of downstream
bacteria isolated from the bivalve, Donax cuneatus. Three processing, technological failures, low yields and toxins
new bacterial strains were identified using difference in production through the process. In this regard, mycotoxin
16S rRNA gene sequence including YP1, OP2 and PYP3. such as citrinin (with orange shade) and other harmful
By chromatography, the purified pigment was recognized secondary metabolites can be produced at the same time
as astaxanthin, which offers cytotoxic effect on MCF-7 with biopigments and consequently the nontoxic pigments
cell lines. The antibacterial potential of the pigments was should be distinguished from colored microbial toxins. To
tested against the pathogens such as S. aureus, E. coli, P. meet the growing demand of the global market, devel-
aeruginosa, Bacillus subtilis and Klebsiella pneumoniae, opment of improved microbial strains and optimization
by measuring zone of inhibition in disc diffusion method. of cultivation parameters are required to obtain a more
According to the results, PYP3 and OP2 strains exhibited effective purification method. Moreover, genetic engi-
greater inhibition zone. The violet pigment extracted from neering techniques should be investigated to optimize the
OP2 strain, which was identified as Chromobacterium vio- biopigment production. Considering the recent advances
laceum, presented effective antibacterial activity against made in the application of agro-industrial waste like lig-
B. cereus, S. aureus, E. coli and P. aeruginosa. This violet nocellulosic biomass such as nitrogen and carbon sources,
pigment presented an 18 mm and 17 mm inhibition zone the low-cost industrial scale production of biopigments
toward S. aureus and K. pneumoniae, respectively, which is possible in near future. In addition, new studies have
were the greatest values [64]. focused on explaining the action mechanism of pharma-
cological aspects of biopigments, which would be actually
useful in discovering novel approaches for the survival of
Antiviral activity human beings against perilous diseases like cancer. In this
way, future surveys should be more directed on the chemi-
Suryawanshi et al. [65] demonstrated a distinctive antivi- cal structure of microbial pigments and the association
ral effect of prodigiosin, produced by S. marcescens, on between their structures and pharmacological function.
herpes simplex virus (HSV) infection. The results indi-
cated that prodigiosin treatment provides a vigorous inhi- Acknowledgements This study is related to the project no. 1398/9812
bition of viral duplication in vitro and ex vivo in cultured from Student Research Committee, Shahid Beheshti University of
Medical Sciences, Tehran, Iran. We also appreciate the “Student
porcine corneas. Moreover, in ocular infection of murine, Research Committee” and “Research & Technology Chancellor”
prodigiosin initiated protection against HSV-1 infection. in Shahid Beheshti University of Medical Sciences for their finan-
For a better description of the inhibition mechanism, pro- cial support of this work. Laurent Dufossé deeply thanks the Conseil
digiosin effect on NF-κB was scrutinized during infection. Régional de La Réunion, Indian Ocean, for continuous financial sup-
port of research projects dedicated to microbial pigments and shows
Initially, 0.6 μM of prodigiosin was used as a suboptimal gratitude to Mireille Fouillaud and Yanis Caro for many years of close
dose to study its mechanism in vitro where viral repli- association in microbial pigments research
cation is permissible. The results revealed that HSV-1
infection of HCE cells could make a vigorous increase Authors' contributions MAM had the idea for the article, MAM and
in NF-κB activity and this was confirmed by using an HA performed the literature search and data analysis, MAM, HA and
SM drafted and critically revised the work. SMH and LD reviewed the
NF-κB-inducible luciferase reporter plasmid. Further manuscript and provided technical assistance to keep the manuscript
examination of factors affecting NF-κB activation, mRNA on track.
levels of tumor necrosis factor alpha (TNF-α) were exam-
ined. These findings exhibited that TNF-α mRNA levels Funding This study is related to the project NO. 1398/9812 from Stu-
were downregulated because of the prodigiosin treatment dent Research Committee, Shahid Beheshti University of Medical Sci-
ences, Tehran, Iran.
after HSV-1 infection, and this implies that prodigiosin
may deliver antiviral activity through inhibition of TNF- Availability of data and material Not applicable.
α-induced anti-apoptotic mediated activity and prosur-
vival gene regulation [65]. Code availability Not applicable.

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10 Bioprocess and Biosystems Engineering (2022) 45:1–12

Declarations 17. Yang, Y., N. Bu, S. Wang, J. Zhang, Y. Wang, and C. Dong,
Carotenoid Production by Caterpillar Medicinal Mushrooms,
Cordyceps militaris (Ascomycetes), under Different Culture Con-
Conflict of interest The authors state that they have no conflicts of in-
ditions. International Journal of Medicinal Mushrooms, 2020.
terest to declare.
22(12).
18. Kalra R, Conlan XA, Goel M (2020) Fungi as a potential source
of pigments: harnessing filamentous fungi. Front Chem 8:369
19. Khan, A.A., A.M. Alshabi, Y.S. Alqahtani, A.M. Alqahtani, R.
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