Received: 22 February 2021 | Revised: 6 April 2021 | Accepted: 18 April 2021

DOI: 10.1002/jobm.202100101

REVIEW

High‐level production of microbial prodigiosin: A review

Rui Han | Roujin Xiang | Jinglin Li | Fengqing Wang | Chuan Wang

College of Bioengineering, Sichuan

University of Science and Engineering, Abstract
Zigong, China Prodigiosin is a natural red pigment derived primarily from secondary meta-
Correspondence
bolites of microorganisms, especially Serratia marcescens. It can also be che-
Chuan Wang, College of Bioengineering, mically synthesized. Prodigiosin has been proven to have antitumor,
Sichuan University of Science and antibacterial, antimalaria, anti‐insect, antialgae, and immunosuppressive ac-
Engineering, Zigong 643000, China.
Email: watpc57944@[Link] tivities, and is gaining increasing important in the global market because of its
great potential application value in clinical medicine development, environ-
Funding information mental treatment, preparation of food additives, and so on. Due to the low
The Sichuan University of Science &
efficiency of prodigiosin chemical synthesis, high‐level prodigiosin of pro-
Engineering Innovation and
Entrepreneurship Training Program for duction by microorganisms are necessary for prodigiosin applications. In this
College Students, Grant/Award Number: paper, the production of prodigiosin by microorganism in recent decades is
S202010622073; The Innovation Fund of
Postgraduate, Sichuan University of
reviewed. The methods and strategies for increasing the yield of prodigiosin
Science & Engineering, are discussed from the aspects of medium composition, additives, factors af-
Grant/Award Number: y2020065 fecting production conditions, strain modification, and fermentation methods.

KEYWORDS
fermentation condition, high‐level production, medium composition, prodigiosin, strain
modification

1 | INTRODUCTION β‐carotene [5], astaxanthin [6], melanin [7], riboflavin

[8], and so on.
Pigments are substances that give an organism a variety Red pigment prodigiosin is a microbial secondary me-
of colors. Pigments are widely used as additives, color- tabolite with an iconic methoxypyrrole skeleton. In recent
ants, and antioxidants in food, textiles, cosmetics, medi- years, prodigiosin has attracted increasing attention due to
cine, and other fields. The main sources of pigment are its versatile beneficial properties. prodigiosin can be used as
natural pigment and synthetic pigment [1]. In recent a food additive to play a bactericidal, dyeing and pre-
years, with the development of society, the demand and servative role in food processing and preservation [9]. In the
output of pigment are on the rise. Because some syn- textile industry, the chemical fiber fabrics dyed with
thetic pigments have toxicity, allergy, mutagenicity, car- prodigiosin has the advantage of washable, high color
cinogenesis, and other problems, alternative healthy and fastness, washable resistance to washing, acid, alkali, and
harmless natural pigments are attracting more and more detergents resistance [10–12]. Prodigiosin can effectively
attention from all over the world [2]. Natural pigments downregulated the expression of microcystin McyB gene
mainly come from plants or microorganisms. Compared and lysed bloom Microcystis aeruginosa [13,14]. Adding
with plant pigments, microbial pigments have some ad- prodigiosin to the feed of rabbits reduced the inflammatory
vantages such as stable, low cost, high yield, and easy cytokines of rabbits under heat stress, and improved ef-
downstream processing, they are suitable substitute for fectively the growth and health status of rabbits [15]. Re-
synthetic pigments [3]. At present, natural pigments cent studies have shown that prodigiosin is an effective
produced by microorganisms include prodigiosin [4], apoptotic agent against a variety of target cells, including a
J Basic Microbiol. 2021;1–18. [Link] © 2021 Wiley‐VCH GmbH | 1
2 | HAN ET AL.

variety of drug‐resistant cells, with little toxicity to normal A number of related reviews summarized the progress made
cell [16]. Prodigiosin has inhibitory effects on a variety of over the decades. These reviews covered the structure,
cancer cells. Prodigiosin showed strong anticancer activity sources, synthesis pathways, production, purification, and
against cancer cell MCF7 (human breast adenocarcinoma), application of prodigiosin [25–28]. These literatures, how-
A549 (human lung carcinoma), and Hep G2 (human he- ever, generally devoted a lot of space to discussing the ap-
patocellular carcinoma), which were 2.75, 1.67, and 3.25 plication of prodigiosin and there is no comprehensive
times as effective as mytomycin C (a commercial anticancer review focus on the production of prodigiosin. Based on this,
compound), respectively [17]. In addition, prodigiosin this paper, starting from the source and synthesis pathway of
showed excellent performance in antifungal [9], anti- prodigiosin, made a full‐scale review and discussion on the
bacterial [18], antiprotozoan [19], antimalaria [20], and high‐level production of prodigiosin, highlighting the use of
ultraviolet protection [21]. media supplement and agroindustrial wastes in high‐yield
Prodigiosin can be synthesized by chemical synthesis and prodigiosin, analyzing the various influence factors, and
microorganism production. Chemical synthesis has many summarizing for the first time the application of genetic
steps, expensive reaction and low synthesis rate. While mi- engineering in prodigiosin production. The paper could
crobial production of prodigiosin is regarded as the future provide effective strategies for large‐scale production of
development direction because of its advantages of en- prodigiosin.
vironmentally friendly, mild conditions, low cost, and easy
industrialization [22]. However, at present, there are still
some problems in microbial production of prodigiosin, such 2 | M I C R O B I A L SO U R C E
as low yield and high cost of extraction and purification
process [23]. The high price of reagent grade prodigiosin and Prodigiosin, bearing the chemical formula C20H25N3O, is a
its derivatives restricts its application research to a certain tripyrrole molecule consisting of pyrrole (A ring), 3‐
extent, which is not conducive to the large‐scale experiment methoxypyrrole (B ring), and 2‐methyl‐3‐pentylpyrrole (C
and the development of clinical experimental drugs. There- ring). Further studies showed that the tripyrrole structure of
fore, in the past few decades, many researchers have focused prodigiosin can also form linear and ring derivatives, which
on increasing the yield of prodigiosin, and a lot of research together constitute the prodigiosin family prodiginines
has been done on its development and application [24]. (Figure 1).

F I G U R E 1 Prodigiosin and its derivatives. (a) Prodigiosin; (b) undecylprodigiosin; (c) streptorubin B; (d) cycloprodigiosin;
(e) metacycloprodigiosin; (f) 2‐(phydroxybenzyl)prodigiosin
HAN ET AL. | 3

Prodigiosin was first discovered in Serratia marcescens tripyridine derivative, undecylprodigiosin, which is
[29]. In recent decades, prodigiosin has been found in a structurally similar to prodigiosin, and a ring derivative
variety of microorganisms. Apart from S. marcescens, there metacycloprodigiosin, with the ratio of 1:1 [41]. S. coeli-
are other Serratia species that produce prodigiosin include color was found to produce undecylprodiginine and
Serratia nematodiphila, Serratia plymuthica, and Serratia streptorubin B, another ring derivative, in a 2:1 ratio [46].
rubidaea. In addition, the accumulation of prodigiosin was Another source of prodigiosin are the endophytic and
also found in Pseudoalteromonas rubra, Vibrio sp., Janthi- symbiotic bacteria of some plants and lower animals.
nobacterium, Pseudomonas putida, Hahella chejuensis, Endophytes have been reported mainly from sponge,
Streptomyces coelicolor, and so on (Table 1). Chamaecyparis lawsoniana and Beta vulgaris L. (Table 1).
These bacteria produced different amounts of prodi- New prodigiosin derivatives are often produced in these
giosin. Prodigiosin production in S. marcescens is usually bacteria and the formation of these products may be re-
higher. The highest recorded original yield of prodigiosin lated to the synthetic genes of the bacteria itself.
was 49.5 g/L from a S. marcescens UCP 1549 which was
isolated from a semiarid soil [30]. The wild strains pro-
ducing prodigiosin were mainly isolated from the sea, 3 | S Y N T HE S I S PA T H W A Y
freshwater lakes, soil, and other places (Table 1). Ac-
cording to current literature reports, S. marcescens iso- As a result of the wide range of bioactivity of prodigi-
lated from soil is still the most promising bacterium for nines, many studies on prodiginines biosynthesis have
producing prodigiosin [30,33,45]. been reported in the past decades. Through a set of
Besides this, some bacteria produce derivatives of analysis which includes homology detection among en-
prodigiosin. Streptomyces sp. produced a linear zymes, repressing the genes to identify its function,

TABLE 1 The microbial source of prodigiosin

Original yield
Source Microorganism Product (mg/L) Reference
Semiarid soil, Brazil Serratia marcescens UCP 1549 Prodigiosin 13500 [30]
Pangola grass compost, Mexico S. marcescens Prodigiosin <13 [23]
Fields contaminated with S. marcescens MO‐1 Prodigiosin 40.12 [31]
pesticides, Turkey
Soil, China S. marcescens FZSF02 Prodigiosin 1735.53 [32]
Soil sample, India S. marcescens CF‐53 Prodigiosin 8500 [33]
Moldy tofu, China S. marcescens Xd‐1 Prodigiosin 1140 [34]
Soils, Vietnam S. marcescensc TNU01 Prodigiosin 2450 [17]
Chamaecyparis S. marcescens subsp. Prodigiosin ND [35]
lawsoniana, USA lawsoniana
Beta vulgaris L., India S. marcescens Prodigiosin ND [36]
Soil sample, India Serratia nematodiphila Prodigiosin 50 [37]
Waterfall, Malaysia S. nematodiphila YO1 Prodigiosin 7.9 [38]
Rhizospheric soil of sorghum, S. nematodiphila 213C Prodigiosin 1129.7 [39]
India
Spoiled coconut, Indian Serratia rubidaea Prodigiosin 3.7 [40]
Sponge Mycale plumose, China Streptomyces sp. Undecylprodigiosin, 12.5 [41]
metacycloprodigiosin
Sponge samples, USA Pseudoalteromonas rubra 2‐(phydroxybenzyl)‐ prodigiosin ND [42]
Lake sediment, Portugal Vibrio spartinae Cycloprodigiosin, prodigiosin ND [43]
Marine sediment, USA Vibrio sp. Prodigiosin ND [44]
Abbreviation: ND, data not available.
4 | HAN ET AL.

analysis of intermediate metabolites, and complementa- a three‐step reaction from the initial precursor, 2‐
tion experiments, the pathways and regulatory mechan- octenoyl CoA, which was formed by the combination of
isms for prodigiosin production in S. marcescens and S. 2‐octenal and pyruvate. Finally, MBC and MAP are
coelicolor are now clear [47,48]. As shown in Figure 2a, condensed by enzyme to form prodigiosin.
two key intermediates, 2‐methyl‐3‐n‐amylpyrrole (MAP) In different bacteria species, the gene clusters in-
and 4‐methoxy‐2,2′‐bipyrrole‐5‐carbaldehyde (MBC), are volved in prodigiosin synthesis vary greatly. For example,
synthesized by bifurcated pathway. In S. marcescens and the Pig cluster and the Red cluster are responsible for the
S. coelicolor, the biosynthesis of MBC begins with the biosynthesis of prodigiosin in Serratia sp. and Strepto-
activation of L‐proline as a thioester and is subsequently myces sp., respectively [47,49]. Other clusters include
converted to the pyrrole ring A of prodigiosin. In the Hap cluster from H. chejuensis [14] and Tam cluster from
upcoming steps, C2 unit provided by malonyl CoA, C2N Pseudoalteromonas tunicata [50]. The Pig clusters of S.
unit provided by serine, and methyl group provided by marcescens has a certain degree of genomic modular-
S‐adenosylmethionine successively combine with pyrrole ization. The Pig B Pig D Pig E gene encodes the protein
ring A to form MBC. In S. marcescens, MAP is formed in for biosynthesis of MAP, and Pig C is involved in the final

F I G U R E 2 Biosynthesis pathway and gene of prodigiosin. (a) Biosynthetic pathway of prodigiosin. (b) Prodigiosin biosynthesis gene
cluster: Serratia marcescens ATCC 274 and Streptomyces coelicolor A3(2). Blank arrows show the genes encoding proteins required for MBC
biosynthesis. The black‐filled arrows show the genes that code for proteins required for the biosynthesis of monopyrroles. The gene
encoding the condensation enzyme is diagonally filled, and Red G cyclizes undecylprodigiosin to form butyl‐meta‐cycloheptylprodigionine,
which is grid filled. The gene clusters not involved in prodigiosin synthesis are gray‐filled. The regulatory genes Red D and Red Z are filled
with horizontal lines. MBC, 4‐methoxy‐2,2′‐bipyrrole‐5‐carbaldehyde
HAN ET AL. | 5

step of condensation of MAP with MBC to form prodi- the medium need to be adjusted for different strains.
giosin. The rest of the Pig cluster, containing Pig A and Some researchers have tried to screen and optimize
Pig F–Pig N, encodes proteins that are directly or in- culture media for different strains. For example, Chen
directly involved in MBC biosynthesis (Figure 2a,b). et al. [59] determined that the carbon and nitrogen
It is worth noting that the synthesis pathway of MBC source for S. marcescens C3 was starch 6/peptone 4
is highly conserved. All clusters have a specific set of through statistical experimental design methodology,
genes that are homologous to each of the enzymes in- which increased prodigiosin yield by 3.07 times to
volved in the formation of MBC in S. marcescens, sug- 7070 mg/L. Su et al. [60] used the same method to de-
gesting that MBC biosynthesis was a common pathway termine the carbon and nitrogen source for S. marcescens
(Figure 2b). However, the biosynthetic pathway of MAP was 0.454% peptone, 0.5% sucrose, with addition of 0.5%
is completely different. For instance, none of the proteins glycine. Prodigiosin production increased 83.42 times to
involved in MAP biosynthesis in S. marcescens had close 2423.4 mg/L [60]. Using single factor test and orthogonal
homologs in the Red cluster. In addition, Pig C homologs array design, Li et al. [41] determined that the carbon
were found in all clusters such as Red H, Hap C, Tam Q. and nitrogen source for Streptomyces sp. GQQ‐10 was
yeast extract 0.75%, starch 1.4%, glucose 0.6%, and soy-
bean meal 2.5%. Kim et al. [61] used two‐level
4 | HIG H ‐ LEVEL Plackett–Burman statistical design to determine that
F E R M E N T A T IO N P R O D U C T I O N the formulation for H. chejuensis M3349 was sucrose
10.0 g/L, peptone 8.0 g/L, and yeast extract 2.0 g/L, which
High level of microbial fermentation pigment products increased prodigiosin yield by 3.9 times to 2600 mg/L.
depends on excellent microbial strains and effective fer-
mentation methods. As a microbial secondary metabo-
lite, prodigiosin is generally formed in the subsequential 4.2 | Medium supplement to increase
stages of bacterial advancement. Compared with the production
production of other microbial pigments, the production
of prodigiosin depends on a number of factors. In recent Many studies have found that the production of prodi-
decades, many researchers have optimized the produc- giosin can be further increased by adding stimulants or
tion of prodigiosin from the aspects of medium compo- modulators to culture media. These supplements can be
sition, production conditions, fermentation methods, and divided into three categories: nutrients, bacteria, and
microbial strains. carrier media. Some of the supplement used to increase
prodigiosin production are shown in Table 2.
The synthesis of prodigiosin precursor MBC requires
4.1 | Optimization of medium the participation of proline, serine, and methionine.
composition Therefore, the addition of these amino acids may sti-
mulate the production of prodigiosin by increasing the
The composition of medium is essential in the growth of synthesis of precursor MBC. Studies have shown that the
microorganisms and the synthesis of metabolites. Uni- addition of proline, glutamic acid, alanine, and serine in
variate screening was used to optimize carbon and ni- the medium can induce the production of prodigiosin
trogen sources and inorganic components, and then [77,78]. And the addition of methionine shorten the de-
statistical analysis was used to optimize the composition lay period of synthesis of prodigiosin, increased the
of the medium. The results showed that peptone and amount of pigment formation, and reduced the optimal
yeast extract were the best carbon and nitrogen sources concentration of other amino acids [79]. Faraag's study
for S. marcescens to produce prodigiosin. While other showed that the addition of tyrosine was more effective
studies showed that glycerol plays an important role as a than alanine and proline, however, the addition of serine
carbon source in the growth of bacteria and prodigiosin inhibited the production of pigment [62]. Wei et al. [63]
production [51]. In many studies on the production and found that many amino acids containing pyrrole struc-
function of prodigiosin, lysogeny broth medium [52], tures, such as proline histidine and aspartic acid, could
nutrient broth [18,53,54], and peptone glycol medium increase undecylprodigiosin yield, with 10 g/L proline
[37,55–58] were most commonly used to produce prodi- having the best effect of increasing the yield by an as-
giosin. At present, nutrient broth and peptone–glycerol tonishing 833 times. Siva et al. [40] compared the effects
are also commercial prodigiosin production medium. of proline, methionine, leucine, alanine, and their com-
Although the basic medium can be used for prodi- positions on the prodigiosin yield, and the results showed
giosin production by S. marcescens, the composition of that the combination of methionine and proline
 6
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TABLE 2 Medium supplement for prodigiosin production

Microorganism Supplement Medium Prodigiosin yield Increased fold Reference
Serratia marcescens WSE Tyrosine, 0.5% Nutrient broth 21.28 mg/L 2 [62]
Serratia rubidaea Methinone, proline Peptone water 1% 10 mg/L 2.6 [40]
S. marcescens SS‐1 Proline, 10 g/L YE medium 25,000 mg/L UP 833 [63]
S. marcescens FZSF02 Olive oil, 10 ml/L Glucose 5 g/L, peanut powder 10 g/L, beef 15,420.9 mg/L 9.3 [32]
extract 10 g/L
Serratia nematodiphila YO1 Palm oil, 3% Lysogeny broth (LB) 93 mg/L 11.9 [38]
S. marcescens (SRI) Vegetative oil mixture, 4% Casein‐enriched medium 765.1 mg/L NR [64]
S. marcescens SM△R Sunflower oil, 6% MLB medium 790 mg/L PLP 14 [65]
S. marcescens Powdered peanut seed, 2% ND 39,000 mg/L 40 [66]
S. marcesens PP1 Powdered peanut broth, 2% ND 1595.09 mg/L ND [67]
S. marcescens S389 Ethanol, 1.5% Pharmamedia 1.5%–2.0%, 1 ml mineral 3000 mg/L 21.85 [68]
solution
S. marcescens Sunflower oil, 0.5 ml/g substrate, Bacillus subtilis, 0.4 ml/ Wheat bran 240 mg/L 2.3 [69]
g substrate
Streptomyces coelicolor Heat‐killed Lactobacillus rhamnosus, 50 µl YEME medium 9.79 mg/L 6 [70]
S. coelicolor A3(2) MT1110 Dead Staphylococcus aureus, 5% (vol/vol) The minimal medium (HMM) 2.53 mg/L UP 5 [71]
S. marcescens S23 Heat‐killed Escherichia coli cell, 3% Sucrose:peptone (6/4) 4100 mg/L 9 [72]
S. marcescens TKU011 Heat‐killed Lactobacillus paracasei SPP, 1% 1400 mg/L 1.27 [73]
S. marcescens 08 SDS, 500 μg/ml Tryptic soy NR NR [74]
S. coelicolor A3(2) Poly HIPE Modified R5 medium 75 µmol/L 5 [75]
Pseudomonas putida KT2440 Hydrophobic polyurethane LB medium 94 mg/L 78.33 [76]
S. marcescens Xd‐1 Initial moisture content of 83.5%, and 1‐mm particles of Glycerol 1.17 g/g bagasse, soy peptone, 40.86 g/kg dry solid 2 [34]
bagasse, 2 g/250 ml flask 0.33 g/g bagasse
Abbreviations: HIPE, high internal phase emulsion; PLP, prodigiosin‐like pigment; ND, data not available; SDS, sodium dodecyl sulfat; UP, undecylprodigiosin.
HAN
ET AL.
HAN ET AL. | 7

increased the yield of prodigiosin the most, which was type of these compound has not been identified yet. An
about three times higher than that of the control group. alternative explanation is that the direct physical contact
These data support the hypothesis that 5‐carbon amino between S. marcescens and the elicitor cells leads to the
acids such as proline, aspartic acid, and glutamate are elicitation [69]. Since dead cells do not occupy nutrient
involved in the synthesis of the pyrrole group, but the resources and do not affect the growth of pigment pro-
role of alanine remains unclear [77]. ducers, finding novel and efficient elicitor cell will help
The initiator of synthesis of MAP, another precursor to produce prodigiosin more simply, quickly and at low
of prodigiosin, is 2‐octenal, which mainly comes from the cost. Given the antimicrobial properties of prodigiosin, it
oxidation of fatty acids. Therefore, the addition of some may be produced by S. marcescens to protect itself from
fatty acid oil can promote the synthesis of 2‐octanal and potential competitors. Therefore, it is a feasible strategy
MAP and thus increase the prodigiosin production. to select competitive symbiotic bacteria in the growth
These oils included sunflower oil, olive oil, palm oil, and environment of S. marcescens to stimulate it to produce
peanut powder (Table 2). Among them, adding peanut prodigiosin.
powder increased prodigiosin the most, with 39,000 mg/L Other additives are added to the fermentation med-
yield [66]. More than 60% of prodigiosin produced by the ium not as nutrients but as adsorbent carriers to facilitate
addition of olive oil existed in the form of pigment pel- pigment collection and may have the effect of promoting
lets. This is the first report of formation of such pigment pigment secretion. Some carriers used for prodigiosin
pellets, which makes the extraction of prodigiosin easier production have been reported (Table 2). Each of these
and less costly [32]. Although some researchers claimed carriers promoted prodigiosin production by different
that oil with high saturation, such as palm oil, is bene- mechanism. For example, Feng et al. [74] added sodium
ficial to prodigiosin production [66], some oil with high dodecyl sulfate (SDS) to improve the recovery efficiency
unsaturated fatty acid content, such as olive oil, still has of prodigiosin. SDS may bind certain components of the
the effect of promoting prodigiosin, which may be related cell envelope of S. marcescens to form negative macro-
to the characteristics of bacteria. Notably, peanut powder molecular sites, which are required for the condensation
broth can be used as a single medium to produce pro- of positively charged PG or its precursors. Domröse et al.
digiosin without other components, which may be due to [76] added hydrophobic polyurethane into the culture
the rich carbon and nitrogen sources in peanut powder medium to adsorb prodigiosin as foam cubes. After fer-
[67]. In addition, a particular strain, S. marcescens S389, mentation, organic solvents were used to effectively wash
was able to produce prodigiosin using ethanol additives, pigment out of the foam cubes. Xia et al. [34] used ba-
This result has not been previously reported before, gasse as inertia matrices which could adsorbate the nu-
probably because the strain was isolated from ethanol‐ trient in the medium efficiently and the production of
utilizing bacteria [68]. prodigiosin was doubled to 40.86 g/kg dry solid by solid
Microbes in nature exist in complex mixed popula- fermentation.
tions. Microbial interactions in some of these populations
are thought to drive the production of most secondary
metabolites, such as antibiotics [80]. The metabolism of 4.3 | Low‐cost substrate for prodigiosin
the microbes thus can be elicited by introducing extracts production
of cells or parts of the cell wall from natural competitors
of the target bacterium. This elicitation is also used to The high cost of production has limited the commercial
produce prodigiosin. Studies have shown that S. mar- application of prodigiosin, partly because of the ex-
cescens can increase the production of prodigiosin by pensive growth media, so finding a low‐cost substrate is
interacting with other elicitor microbial cells, either alive an effective way to reduce prodigiosin production costs.
or heated dead. Bacteria reported to increase the prodi- Some agroindustrial waste and by‐products still contain
giosin production of S. marcescens included Bacillus significant nutrients such as protein, crude fiber, fatty
subtilis, Escherichia coli, and Lactobacillus paracasei, acids, and minerals. These waste and by‐products have
while those used for S. coelicolor included Lactobacillus been proposed as low‐cost alternative, in whole or in
rhamnosus, and Staphylococcus aureus (Table 2). Among part, carbon and nitrogen sources for microbial metabo-
them, heat‐killed E. coli elicited S. marcescens S23 to lite production, thereby reducing environmental pollu-
increase production of prodigiosin by nine times to tion and developing value‐added products.
4100 mg/L [72]. The mechanism of elicitation is not fully Some of the wastes or low‐value by‐products used in
understood. One explanation is that the elicitor cells production of prodigiosin are summarized in Table 3. As
lysed during culture to release some stimulant or mole- the table showed, the low‐cost substrate used for prodi-
cule, which can act as pigment precursors. However, the giosin production included agricultural wastes, food
 8
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TABLE 3 Low‐cost substrate for prodigiosin production

Microorganism Waste or low‐cost substrate Supplement Prodigiosin yield Increased fold Reference
Serratia marcescens UCP 1549 Cassava wastewater, 6% Mannitol 2% 49,500 mg/L 3.67 [30]
S. marcescens Tannery fleshing (TF) 70TF :30 heat bran 30% (wt/vol) of TF 3.26 [81]
S. marcescens UTM1 Brown sugar, 10% ND 8109 mg/L 33.7 [82]
S. marcescens ATCC 13880 Peanut oil seed cake, 4% Sucrose 2%, casein hydrolysate 1% 900 mg/L 10 [83]
Streptomyces sp. NRCF69 Dairy processing wastewater, 2% Mannitol 1% 47,000 mg/L NR [84]
S. marcescens Crude glycerol, 1% Peptone 1% 1740 unit/cell 3.48 [85]
S. marcescens MO‐1 Ram horn peptone, 0.4% Mannitol 1% 277.74 mg/L 6.9 [31]
S. marcescens TKU011 Squid pen powder, 1.5% FeSO4(NH4)2SO4·6H2O 0.1% 2480 mg/L 3.26 [86]
Serratia AM8887 Fertilizer factory waste, 12 g/L Glycerol 6 g/L, sucrose 6 g/L, yeast extract 1 g/L, NaCl 15 g/L 1805.28 mg/L 1.35 [87]
S. marcescens CF‐53 Peanut oil cake, 8% ND 40,000 mg/L 4.7 [33]
S. marcescens TKU011 α‐Chitin from shrimp shells, 1% Casein 0.6%, KH2PO4 0.05%, CaSO4 0.1% 4620 mg/L 1.69 [17]
S. marcescens TNU01 Squid pen powder, 1.75% K2HPO4 0.03%, MgSO4 0.05% 3450 mg/L 1.4 [88]
S. marcescens TNU02 1.6% C/N source (protein/deCSP (NH4)2SO4 0.02%, K2HPO4 0.1% 5100 mg/L 1.69 [89]
ratio of 3/7)
Achromobacter Blood bag, 1 g K2HPO4 1.0 g/L, NaCl 1.0 g/L, NH4Cl 0.5 g/L, MgSO4 0.4 g/L 1314 mg/L 1.66 [90]
denitrificans SP1
S. marcescens NPLR1 Tannery fleshing, 3% NaCl 0.4 g/L, NH4Cl 0.005 g/L, K2HPO4 1.25 g/L, 1 ml 33,000 mg/L 26.1 [91]
mineral solution
S. marcescens TKU011 Squid pen powder, 1.5% K2HPO4 0.1%, MgSO4 0.05%, 978 mg/L 1.96 [73]
S. marcescens Kitchen waste, 35 g/L Peptone 1%, proline 0.2% 890 mg/L 3.99 [92]
S. marcescens Kitchen waste (KW) Rice husk 1:2 KW, proline 1.5% 4155 mg/kg KW 3.22 [93]
Abbreviation: De‐CSP, demineralized crab shell powder.
HAN
ET AL.
HAN ET AL. | 9

industry processing waste, fishery processing waste, stirring and low rate aeration [96]. For instance,
chemical industry waste and other low‐value by‐ Suryawanshi et al. [97] obtained the highest yield of
products. All of these low‐cost substrate could sig- prodigiosin at 180 rpmin by adjusting the rotating speed
nificantly increase the prodigiosin yield, and the one with of culture oscillator, and the lower or higher rotating
brown sugar, an agricultural by‐product, as the medium speed decreased pigment production. Oxygen consump-
could increase by 33.7 times [82]. These wastes usually tion was higher in the early stage than in the later stage
required the addition of carbon sources such as mannitol of pigment synthesis [98]. Thus, maintaining a high level
or inorganic ions to achieve high levels of production. A of dissolved oxygen in the medium can accelerate the
typical example was the addition of 2% mannitol to 6% growth and fermentation of S. marcescens.
cassava wastewater, with prodigiosin production reach- The pH value is an essential factor in the prodigiosin
ing 49,000 mg/L [30]. In contrast, brown sugar and pea- production of S. marcescens. The pH affects the decom-
nut oil cake could be used as separate carbon and position of substrates and the transport of substrates and
nitrogen sources to replace the culture medium without pigments through the cell wall, and may be related to the
additional additives. Especially, 8% peanut oil cake amount of proline incorporated into prodigiosin [99]. S.
medium could increase the prodigiosin yield to a con- marcescens produce prodigiosin at pH 4–10, but different
siderable 4000 mg/L [33]. This may be due to the fact that strains and media have different requirements for opti-
peanut oil cake is rich in crude protein, crude fiber, vi- mal pH. In most studies, the optimum pH for prodigiosin
tamin, and mineral salts, which can be used as microbial production is between 6 and 8. Generally, prodigiosin
carbon and nitrogen sources for microbial growth. production is high in alkaline initial environment, and
In general, the medium mainly composed of agricultural no prodigiosin is produced when pH is less than 4 or
wastes and by‐products can effectively increase the yield of higher than pH 10 [26]. Acidic external pH conditions,
prodigiosin. Nevertheless, there are still a large number of which was caused by the carbon source effect, decreased
wastes from cereal industry, fruit and vegetable industry, and the synthesis of prodigiosin [100]. Unexpectedly, the acid
dairy industry to be developed as medium for prodigiosin pH shock (pH decreased from 7.2 to 4) increased the
synthesis. In addition, most of the studies in this area production of undecylprodiginine and streptorubin B in
focused on Serratia, and less on non‐Serratia. At present, S. coelicolor M511 by 1.8 times (37.22 mg/g) and 2.5 times
only one study reported that dairy processing wastewater (18.61 mg/g), respectively [46].
medium was used to make prodigiosin production of Production of prodigiosin in S. marcescens is
Streptomyces reach 47,000 mg/L [84]. Thus, replacement of temperature sensitive. When bacteria grow at high
more expensive traditional composite medium with easily temperatures, synthesis of prodigiosin is inhibited.
available agroindustrial waste and by‐products should speed The temperature regulation of prodigiosin production
up the large‐scale production of this useful bacterial is mainly controlled at the transcriptional level.
secondary metabolite. Transcription level of prodigiosin biosynthetic operon
decreased at 37°C compared to 30°C [101]. The opti-
mum temperature for prodigiosin production is
4.4 | Fermentation conditions and usually between 22°C and 30°C. The condensation
influence factors enzyme Pig C, the last step in prodigiosin synthesis, is
temperature sensitive. Pig C denatured above 30°C,
Although the composition of medium can greatly in- preventing the condensation of MAP and MBC to
crease the yield of prodigiosin, the production of prodi- form prodigiosin. Pig C activity decreased below 22°C,
giosin is also affected by many factors such as resulting in reduced pigment biosynthesis [102].
temperature, pH, inorganic salt, and other environmental When the temperature is higher than 37°C, S. mar-
factors. cescens hardly synthesizes prodigiosin [77,95]. How-
Dissolved oxygen is an important factor affecting the ever, the effect of temperature on prodigiosin
production of prodigiosin. S. marcescens requires a large production seems to vary with different medium
amount of dissolved oxygen to produce prodigiosin. composition. For example, Giri et al. [66] found that
Anaerobic conditions would prevent the synthesis of the Serratia cultured with nutrient broth did not
MBC and the condensation of MBC and MAP, thus in- produce prodigiosin at 37°C, while the bacteria cul-
hibiting the formation of pigment [94]. Compared with tured with fatty acid seed medium, such as powdered
anaerobic fermentation, bacteria in aerated medium can peanut broth, produced prodigiosin at 37°C as much
synthesize prodigiosin most effectively [54,95]. Dissolved as at 30°C. Powdered peanut broth could even raise
oxygen can be obtained in flask at a high oxygen transfer the production temperature to 42°C, but the yield was
rate or in fermenter by a combination of high speed lower than what was obtained at 28°C.
10 | HAN ET AL.

Prodigiosin is a photosensitive pigment, and the that the pigment synthesis of V. gazogenes decreased
production of prodigiosin varied with the light intensity when the concentration of KH2PO4 exceeded 0.4 mM.
of Serratia culture. Prodigiosin can absorb light and The mechanism of phosphate may be that it specifically
cause phototoxic damage to cell membranes, thus the interfered with the formation or activity of alkaline
leakage ratio of pigment under light condition is higher phosphatase [112]. However, other researchers suggested
than that under dark condition [103]. Studies have that the inhibitory effect may be due to the precipitation
shown that S. marcescens grow better in the dark than in of calcium, iron and magnesium ions caused by high
light, producing more pigment in cells. With the exten- phosphate levels, resulting in the loss of these ions from
sion of light time, the pigmentation decreased. Pigment the medium [106].
accumulated when the culture conditions switched from Adenosine triphosphate (ATP) and ribose are also
light to dark [98]. inhibitors of prodigiosin biosynthesis. In Serratia, there is
Some trace elements also contribute to the bio- a strong association between growth, ATP levels and
synthesis of prodigiosin in Serratia. The addition of prodigiosin. In the process of constant growth rate cul-
thiamine in peptone–glycerol medium could stimulate ture, the results of pigment induction showed that the
Serratia to produce prodigiosin. Thiamine may be in- cellular prodigiosin level was negatively correlated with
volved in the regulation of MAP biosynthesis [104]. Iron ATP [113]. In high cell density cultures, the activation of
is essential for the growth and pigmentation of S. mar- prodigiosin operon transcription by decreasing cellular
cescens, and more iron is required for prodigiosin bio- ATP levels increased the production of prodigiosin [114].
synthesis than for growth [105]. Furthermore, 0.14 mmol Besides, the production of secondary metabolites in S.
Fe2+ concentration was the best for the growth and marcescens was inhibited by cAMP, which is a negative
pigment production of Vibrio gazogenes [106]. regulator of prodigiosin production in S. marcescens
However, some excessive trace elements can also af- [115,116]. Glucose, on the other hand, inhibits the pro-
fect the biosynthesis of prodigiosin in in Serratia. The digiosin production of S. marcescens [99,117]. This in-
high concentration of NaCl in the medium inhibited the hibition is pH dependent and may be due to the rapid
production of prodigiosin in S. marcescens by osmosis, oxidative breakdown of glucose resulting in a lower pH,
which was because both the synthesis reaction of MBC and thus inhibiting the prodigiosin production through
and the condensation reaction to form prodigiosin are transcriptional control of the prodigiosin biosynthetic
sensitive to NaCl. For example, 3% sea salt NaCl in- operon [99,118]. The inhibition could be reversed by
hibited the prodigiosin synthesis of S. marcescens, and theophylline, an inhibitor of cAMP phosphodiesterase.
the same molar concentration of Na2SO4, KCl, and K2SO4 Similarly, the effect of glucose was also related to com-
had the same effect [105]. While, NaCl over 1.2 M also position of medium and strain. The addition of maltose
affected the production of prodigiosin in S. rubidaea or glucose promoted the production of pigment in a
N‐1.[107]. However, the effects of salt vary by species, nutritious broth that has little carbon source [66]. For V.
and some require the presence of salt for prodigiosin gazogenes, the optimum concentration of glucose for
production. Vibrio isolated from Atacama salt lake re- growth and pigment production was 3.0%. High glucose
sponded to the osmotic stress of 100 g/L NaCl by pro- levels inhibited the synthesis of pigment [106]. In S.
ducing prodigiosin [108]. S. rubinaea N‐1 was a salt‐ coelicolor A3(2), elevated glucose levels stimulated a
tolerant bacterium isolated from seawater, which pro- specific rate of undecylprodigiosin production [111].
duced more prodigiosin under the condition of 0.6–1.0 M
NaCl [107]. And the high salt concentration of 2.5% NaCl
activated the production of undecylprodigiosin by S. 4.5 | Strain modification for high‐yield
coelicolor A3(2) [109]. prodigiosin
Inorganic phosphate can affect the production of
prodigiosin. With the increase of phosphate level, the Excellent strain is the basis of obtaining high yield of
production of prodigiosin in S. marcescens decreased prodigiosin. Wild strains generally produce low amounts
[110]. In addition, increased phosphate concentration of pigment and do not have the ability to produce pig-
also significantly reduced the specific rate of un- ment on a large scale to achieve industrial production.
decylprodigiosin production in S. coelicolor A3(2) [111]. Therefore, the modification of wild strain is a method to
Witney et al. [112] found that S. marcescens could pro- obtain excellent strain with stable and high yield. The
duce more prodigiosin at a phosphate concentration of performance of the modified strains was better than that
less than or equal to 0.3 mM, and prodigiosin production of the wild strains. These strains were used as the ori-
was significantly reduced between 10 and 250 mM of ginal strains to optimize the medium composition and
phosphate concentration. While Allen et al. [106] found culture conditions, which would further improve the
HAN ET AL. | 11

prodigiosin yield. The methods of strain modification Although mutagenesis has good effect, it has some de-
mainly include mutagenesis and genetic engineering fects such as low frequency of beneficial mutation and
mutation. difficult to control the direction and property of muta-
Mutagenesis can improve the mutation rate in a short tion. In addition, some novel mutagenesis methods, such
time and obtain better phenotypes. The methods of as ion‐beam injection, atmospheric and room tempera-
mutagenesis include physical mutagenesis and chemical ture plasma and laser are still to be used in the muta-
mutagenesis. Some strains have improved the perfor- genesis of S. marcescens. And the combined treatment of
mance of prodigiosin production by mutagenesis several mutagens is also a potential research direction to
(Table 4). Most of the reported mutagenesis cases were improve prodigiosin production.
focused on S. marcescens. Physical mutagenesis for S. Genetic engineering can target change host genes to
marcescens included ultraviolet [51,119], microwave [10], obtain the required genotype, which has great advantages
and gamma radiation [85]. Chemical mutagenesis in the biosynthesis of prodigiosin. There are two strate-
methods were mainly use ethyl methane sulfonate [61] gies to improve prodigiosin yield by using genetic en-
and methyl nitrosoguanidine [120]. These methods are gineering. The first is to delete related genes in
simple and effective, and the prodigiosin production of prodigiosin‐producing bacteria. There have been many
wild strains has been increased to varying degrees. reports on improving the prodigiosin production ability

TABLE 4 Strain modification for high‐yield prodigiosin

Host strain Method Yeild Increased fold Reference
Serratia marcescens UV mutagenesis 45.93 mg/L 3.15 [119]
S. marcescens UV mutagenesis 96.5 mg/L 2.8 [51]
S. marcescens Microwave mutagenesis 6500 mg/L 2.09 [10]
S. marcescens Gamma irradiation mutagenesis 1740 unit/cell 2 [85]
S. marcescens EMS mutagenesis 137.08 mg/L 8 [119]
Hahella chejuensis EMS mutagenesis 1628 mg/L 2.5 [61]
KCTC 2396
Vibrio gazogenes Methyl nitrosoguanidine mutagenesis ND 1.81 [120]
S. marcescens JNB5‐1 Disruption of dacA 227.94 mg/L 3.89 [121]
S. marcescens JNB5‐1 Disruption of CpxR, integrate a fusion of 5830 mg/L 1.42 [122]
proC, serC, and metH
Streptomyces Deletion of pfkA2 Produce UP, NR 2‐6 [123]
coelicolor A3(2)
S. coelicolor Deletion of ohkA, CDA, Act gene cluster, 96.8 mg/g 12 [124]
integrate Red BGC
S. coelicolor Deletion of CDA, Act gene cluster NR 5 [125]
and rrdA
Streptomyces lividans Introduce afsB from S. coelicolor A3(2) 170 µg/g mycelia, UP ND [126]
Erwinia carotovora Integrate pig cluster of S. marcescens Prodigiosin pigmentation was ND [127]
ATCC 39006 observed
Pseudomonas putida Integrate pig cluster of S. 94 mg/L 78.33 [76]
KT2440 marcescens W838
Escherichia coli K‐12 Introduce Sau3A fragments of S. Prodigiosin produced with ND [128]
marcescens (Nima) DNA addition of precursor
E. coli Introduce hap cluster of H. chejuensis Prodigiosin production was ND [129]
KCTC 2396 observed
Abbreviations: BGC, biosynthetic gene clusters; CDA, calcium‐dependent antibiotic; EMS, ethyl methane sulfonate; ND, data not available; UP,
undecylprodigiosin.
12 | HAN ET AL.

of host bacteria by deleting or disrupting negative reg- marcescens were introduced into Erwinia carotovora
ulatory genes (Table 4). Pan et al. [121] enhanced the [127] or E. coli K‐12 [128]. Beside this, the prodigiosin
prodigiosin leakage by disrupting D‐Ala‐D‐Ala carbox- production was also observed by introducing the hap
ypeptidase gene dacA of S. marcescens, thereby reducing cluster of H. chejuensis KCTC 2396 into E. coli and up-
the feedback inhibition of prodigiosin and increasing the regulating the positive regulators [129].
expression of the Pig cluster. The prodigiosin production These studies revealed the characteristics of the pro-
of S. marcescens JNB5‐1 increased by 3.89‐fold [121]. In digiosin synthesis pathway and the role of some reg-
another study, Sun et al. [122] disrupted the ompR family ulatory factors. Biosynthesis of prodigiosin has been
transcriptional regulator cpxR of S. marcescens JNB5‐1 achieved in well‐established host cells, thus establishing
and increased the transcription level of Pig cluster and an effective method for heterogenous biosynthesis of
prodigiosin precursor pathway related genes. They also prodigiosin, which can provide the basis for the large‐
integrated a fusion segment of proC, serC, and metH, scale synthesis of this pigment and provide a platform for
which are responsible for compound of proline, serine, further research on heterogenous biosynthesis. Even so,
and methionine, and thus the prodigiosin production the yield of prodigiosin obtained by genetically en-
increased by 41.9% to 5830 mg/L. For S. coelicolor A3(2), gineered bacteria was still very low, and further studies
Borodina et al. [123] achieved high production of un- on the molecular mechanism and regulation of prodi-
decylprodigiosin by deleting pfkA2 encoding phosphoo- giosin synthesis are still necessary.
fructokinase. Based on the deletion of actinorhodin and
calcium‐dependent antibiotic biosynthetic gene cluster of
S. coelicolor, Zhang et al. [125] further deleted the ne- 4.6 | Fermentation mode of prodigiosin
gative regulator of Red production rrdA, so that the final production
prodigiosin (Red) yield by the engineered strain was
more than five times that of the wild‐type strain. How- The production of microbial pigments is a fermenta-
ever, Liu et al. [124] further deleted the Red biosynthesis tion process from laboratory Petri dish to large‐scale
repressor gene ohkA, encoding orphan histidine kinase, industrial production. The process of bacterial fer-
and multicopy integrated Red biosynthetic gene cluster. mentation is regulated by the complex interaction
The Red yield of the S. coelicolor mutant was doubled between the physical, chemical, and biological con-
compared with that of the wild‐type strain S. coelicolor ditions of fermentation environment and intracellular
M145. biochemical reaction. Therefore, the design of the
Since S. marcescens is a conditional pathogen, large‐ fermentation mode should consider the factors such
scale cultures of S. marcescens for synthesis of prodigio- as substrate features, strain characteristics, product
sin are potentially risky. And the long incubation period properties, and production conditions. The microbial
required by S. marcescens to synthesize prodigiosin also production of prodigiosin is usually by liquid fer-
leads to the high production cost. Another strategy for mentation culture, but some researchers used solid
genetic engineering is to transfer the prodigiosin path- state fermentation culture. For example, de Araujo
way from the original host to a host that meets industry et al. [30] prepared solid culture plates for S. mar-
standards. So far, expression of pathway proteins and cescens by adding 1.5% agar to cassava wastewater,
production of prodigiosin have been realized in some the prodigiosin yield of 49.5 mg/ml was obtained
model bacteria (Table 4). For example, Horinouchi et al. by the fermentation of S. marcescens at 28°C.
[126] introduced afsB, a regulatory gene controlled po- Arivizhivendhan et al. [130] used wheat bran and
sitively the biosynthesis of pigments, from S. coelicolor limed tannery fleshing to prepare solid medium, and
A3(2) into Streptomyces lividans, significantly producing the prodigiosin yield reached 88.91 g/kg.
undecylprodigiosin that the original host could not pro- The various fermentation strategies used in the produc-
duce under the same culture conditions. In other studies, tion of microbial biological products include batch fermen-
prodigiosin production has been achieved mainly by in- tation, continuous fermentation, immobilized culture, and
troducing the synthetic pathway gene clusters of bioreactor culture. These methods have been reported pre-
prodigiosin‐producing bacteria into host cells. Some ty- viously in the production of prodigiosin. Tao et al. [51] in-
pical cases include: Domröse et al. [76] integrated Pig creased the yield of prodigiosin by 7.8 times by adding
cluster of S. marcescens into the chromosome of P. putida glucose first and then glycerin in batch feeding of fermen-
KT2440. Under the control of the host strong promoter, tation. Fu et al. [131] used foam flotation method for con-
the maximum yield of prodigiosin reached 94 mg/L [76]. tinuous fermentation, which automatically concentrated
And the pigmentation of prodigiosin was observed when cells and prodigiosin in the foam, simplified extraction and
the Pig cluster or Sau3A fragments of Pig cluster from S. achieved high production. Compared with batch feeding
HAN ET AL. | 13

fermentation, prodigiosin yield increased by 2.70 times. At restricting the application of prodigiosin. Therefore, in-
present, most of the fermentation strategies for prodigiosin creasing production efficiency and reducing production cost
production adopt batch culture. are the prerequisites for the practical application of prodi-
Immobilized bacteria in a special carrier can promote giosin. Based on this, we, from the perspective of high‐level
bacterial proliferation and prodigiosin production. The production of prodigiosin, comprehensively reviewed the
reported carriers for the immobilization S. marcescens ideas and achievements of researchers in improving prodi-
included silica gel [132], aerosols [133], and calcium al- giosin production, and focused on the progress in medium
ginate beads [59]. Among them, S. marcescens C3 was additives, low‐cost medium application, fermentation influ-
coated with 3% calcium alginate beads and then added to encing factors, and the production of genetically engineered
the culture medium for fermentation. The yield of pro- bacteria. Our summary will be helpful for researchers to take
digiosin was doubled to 15,600 mg/L [59]. targeted measures for high level prodigiosin production. For
The bioreactor suitable for industrial fermentation is a the study of prodigiosin, there still need to be breakthrough
necessary condition to increase the yield of pigment, and can progress in the screening of excellent original strains, de-
also provide convenience for downstream separation and termination of low‐cost medium of industrial grade, opti-
purification. For example, Aruldass et al. [82] used brown mization of fermentation conditions and gene regulation.
sugar as a low‐cost medium to produce prodigiosin in a 5 L
agitator bioreactor with a yield of 8109 mg/L. Naik et al. [33] AC KNOW LEDGM ENTS
used peanut oil cake as a low‐cost medium to obtain pro- This study was supported by the Innovation Fund of Post-
digiosin up to 40,000 mg/L in a 2 L bioreactor. On the other graduate, Sichuan University of Science & Engineering
hand, some bioreactors are dedicated to convenient and ef- (y2020065), and the Sichuan University of Science & En-
ficient recovery of prodigiosin. Kim et al. [134] developed an gineering Innovation and Entrepreneurship Training Pro-
in situ bioreactor with HP‐20 resin external extraction col- gram for College Students (S202010622073).
umn to recover prodigiosin, which increased the yield by
1.31 times compared with the simple batch culture and C O NF L I C T O F I N T E R E S T S
reached a maximum yield of 6,920 mg/L. Song et al. [135] The authors declare that there are no conflict of interests.
designed a novel integrated bioreactor with internal ad-
sorbent (HP‐20 resin) to improve the prodigiosin yield, and DATA AVAILABILITY STATEMENT
make the prodigiosin easy recovery. Similarly, Bae et al. The data that support the findings of this study are available
[136] used a bioreactor with internal adsorbent to recover from the corresponding author upon reasonable request.
prodigiosin with a concentration of 13.1 g/L, which was 1.8
times that of pigments recovered by the bioreactor with ex- ORC ID
ternal adsorbent. In addition, Nguyen et al. [89] suggested Chuan Wang [Link]
that the production of prodigiosin in bioreactor systems re-
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