Asian Pacific Journal of Tropical Biomedicine

: 2022  |  Volume : 12  |  Issue : 6  |  Page : 233--242

Prodigiosin from Serratia: Synthesis and potential applications

Sami Mnif1, Marwa Jardak1, Brahim Bouizgarne2, Sami Aifa1,  
1 Laboratory of Molecular and Cellular Screening Processes, Centre of Biotechnology of Sfax, University of Sfax, PO box 1177, Road Sidi Mansour km 6, 3018 Sfax, Tunisia
2 Laboratory "Plant Biotechnology", Department of Biology, Faculty of Sciences, University Ibn Zohr, B.P 8106, 80000 Agadir, Morocco

Correspondence Address:
Sami Mnif
Laboratory of Molecular and Cellular Screening Processes, Centre of Biotechnology of Sfax, University of Sfax, PO box 1177, Road Sidi Mansour km 6, 3018 Sfax


Prodigiosin is a red pigment with a pyrrolylpyrromethane skeleton. It is mainly produced by bacterial strains belonging to the Serratia genus, but also by some other genera, including Streptomyces and Vibrio. Within the genus Serratia, the pigment is generally produced as a virulence factor. However, it also has many important beneficial biological activities such as immunosuppressive and anti- proliferative activities. Moreover, the pigment has many industrial applications in textile and cosmetics. In this mini-review, we discuss the genetic and molecular mechanisms supporting prodigiosin synthesis and production from the Serratia genus, as well as its potential applications.

How to cite this article:
Mnif S, Jardak M, Bouizgarne B, Aifa S. Prodigiosin from Serratia: Synthesis and potential applications.Asian Pac J Trop Biomed 2022;12:233-242

How to cite this URL:
Mnif S, Jardak M, Bouizgarne B, Aifa S. Prodigiosin from Serratia: Synthesis and potential applications. Asian Pac J Trop Biomed [serial online] 2022 [cited 2022 Jul 2 ];12:233-242
Available from:

Full Text

 1. Introduction

Among natural products, secondary metabolites are obtained from two main sources: plants, and microorganisms. As secondary metabolites, they are generally classified as low molecular weight products that have generally little or no proven function in cell vital metabolisms. Secondary metabolites produced and secreted by microorganisms are of great interest. Certainly, these metabolites have numerous pharmaceutical properties, which will benefit human health and nutrition as well as add economical value. Biopigments, produced either by microorganisms or plants, are among the most abundant classes of secondary metabolites[1]. As a result of their stability and year-round availability, biopigments from microorganisms have been preferred over those from plants. Conversely, plant biopigments suffer from many disadvantages, such as being unstable to heat and light. Prodigiosin is one of these microbial biopigments[1]. Prodigiosin is considered an important molecule since it has been applied in various fields and represents a promising area of research. Prodigiosin belongs to a family of natural red pigments (prodiginins) of low molecular weight (323.4 Daltons) that appear only in the later stages of bacterial growth called idiophase. Prodigiosin (C20H25N3O) is produced by many strains of Serratia spp. It is associated with extracellular vesicles or found in intracellular granules[1].

Prodigiosin is a member of the prodiginines[2]. It is a hydrophobic compound with a Log POW of 5.16[3] and has been reported as responsible for cell surface hydrophobicity in various Serratia strains[4]. The prodigiosin group belongs to the tripyrrole family, which contains a 4-methoxy, 2-2 bipyrrole ring. Its biosynthesis is a two-step process in which the mono- and bipyrrole precursors are first synthesized as two distinct units and then combined to form the final product, prodigiosin [Figure 1][5]. In this review, we investigate the exact mechanism of prodigiosin production, including structural pathways, molecular regulation in Serratia strains, and potent biological activities of this versatile compound. Moreover, the recent advances in large-scale production of prodigiosin are also discussed.{Figure 1}

 2. Prodigiosin-producing microorganisms

Prodigiosin has long been a subject of research interest because of its many potential beneficial properties. It belongs to the family of prodiginins [Figure 2]. This metabolite is secreted by several microorganisms such as Vibrio ruber[6], Hahella chejuensis[7], Zooshikella sp.[8], Streptomyces coelicolor[9], Streptomyces griseoviridis[ 10], Serratia nematodiphila[11], Serratia rubidaea[12] and Serratia marcescens (S. marcescens)[13]. The most widely known source is S. marcescens[14].{Figure 2}

 3. Prodigiosin synthesis

As shown in [Figure 3], the biosynthesis of prodigiosin results from the condensation of two key intermediates, 2-methyl-3-n-amylpyrrole (MAP) and 4-methoxy-2-2’-bipyrrole-5-carbaldehyde (MBC)[15].{Figure 3}

3.1. Biosynthesis of MAP fragment

The original precursor to this pyrrole is oct-2-enal, which can be obtained by fatty acid transformations. When oct-2-enal reacts with pyruvate in the presence of thiamine pyrophosphate, it produces CO2 and 3-acetyloctanal [Figure 4]. In the presence of amino acid, an aminotransferase produces the cyclic imine H2MAP. This imine is eventually oxidized by a flavin (flavin adenine dinucleotide) to MAP[16] [Figure 4].{Figure 4}

3.2. Biosynthesis of MBC fragment

The first step in the synthesis of MBC is the conversion of proline to a pyrrole via a thioester intermediate. ATP activates and transfers it to a thiol of a PCP transport protein (peptidyl carrier protein) [Figure 5]. This compound undergoes double oxidation with flavin adenine dinucleotide, to lead to the pyrrole core. The pyrrole moiety is transferred to an active site of cysteine and then to a malonyl group. The latter has been previously decarboxylated and is derived from the malonyl-CoA complex. Thus, the pyrrolyl-P- ketothioester is formed. Condensation of a serine gives 4’-hydroxy- 2,2’-bipyrrole-5-methanol by transamination. The primary alcohol in 4’-hydroxy-2,2’-bipyrrole-5-methanol is oxidized to carboxaldehyde. Methylation occurs with a methyltransferase from S-adenosylmethionine (AdoMet) to provide the MBC fragment[16] [Figure 5].{Figure 5}

 4. Genetic organization of the group of biosynthetic genes of prodigiosin

The pig cluster comprises 14 genes and is 20 960 bp in size. These genes are arranged in the order of pigA, pigB, pigC, pigD, pigE, pigF, pigG, pigH, pig1, pigJ, pigK, pigL, pigM and pigN [Figure 6][16]. The function of each corresponding protein is listed in [Table 1]. The green arrows indicate the genes involved in the biosynthesis of the monopyrrole fragment, MAP, while the blue arrows represent the genes involved in the synthesis of the bipyrrole group, MBC. The red arrow is the gene that encodes for the terminal condensation enzyme, pigC. Transcriptional regulators of prodigiosin expression are indicated by yellow arrows [Figure 6]. PigG and pigA are involved in the early steps of MBC biosynthesis[17]. PigJ and pigH are involved in the biosynthesis of MBC[16]. All genes encoded for known proteins except pigK for which no assigned function is known[16],[18]. Indeed, in Serratia, deletion of pigK has no effects on prodigiosin production. It was suggested that pigK may have a role in assisting the folding of one or more of the Pig enzymes involved in the later stages of MBC biosynthesis[18].{Figure 6}{Table 1}

 5. Control of prodigiosin production by quorum sensing

Generally, prodigiosin production is controlled by the quorum- sensing regulatory system, which controls biofilm formation and virulence factor production in Serratia and other bacterial genera.

In Serratia sp. ATCC 39006, prodigiosin production is regulated by the SmaI/SmaR quorum-sensing system and its cognate N-acylhomoserine lactones, N-butanoyl-L-homoserine lactone (C4-HSL), and N-hexanoyl-L-homoserine lactone (C6-HSL), the former being the more abundant molecule[19]. SmaR is a repressor of Pig when the levels of N-acyl-L-homoserine lactones, produced by SmaI, are low[17]. At low cell density, transcription of the pig cluster is repressed by SmaR, whereas at high cell density, binding of C4-HSL/C 6-HSL to SmaR derepresses transcription. In addition, the production of prodigiosin also depends on quorum sensing system within the strain of S. marcescens SS-1. The regulation of prodigiosin production is coordinated by two LuxI/LuxR homologues which are SpnI/SpnR. Autoinducers involved in this regulation were identified as 3-oxo-C6HSL, C6-HSL, C7-HSL, and C8-HSL[20]. More recent investigations showed that a PigP has a significant regulatory role in Serratia sp. ATCC 39006 and acts by binding to DNA (transcriptional regulator). It also seems that environmental conditions mainly phosphate availability could regulate prodigiosin synthesis[21].

 6. Medical, pharmaceutical, and industrial applications of prodigiosin

Prodigiosin has recently received great attention for its wide range of biological activities, including antimalarial, antifungal, and antibiotic activities. Moreover, it also has anti-cancer, and anti- metastatic properties and is best known for its ability to trigger apoptosis in cancer cells. However, the molecular mechanisms responsible for these abilities are not fully understood[22]. Some of these activities and applications are detailed below.

6.1. Antimicrobial activity

6.1.1. Antibacterial activity

The antibacterial activity of prodigiosin is higher against Gram- positive bacteria such as Staphylococcus aureus, Staphylococcus saprophyticus, Bacillus subtilis, Enterococcus avium, and Streptococcus pyogenes compared to Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, and Klebsiella aerogenes[22],[23]. Prodigiosin has also been shown to be effective against Borrelia burgdorferi, the causative agent of Lyme disease[24]. Hage-Hülsmann et al. reported the minimum inhibitory concentration (MIC) value of prodigiosin against Corynebacterium glutamicum of 2.56 μg/mL which was improved in the presence of N-myristoyltyrosine to 0.005 μg/mL[25]. It has been demonstrated that the antibacterial activity of prodigiosin arises from its ability to cross the outer membrane and inhibit target enzymes such as DNA gyrase and topoisomerase IV, thus blocking cell growth by generating reactive oxygen species (ROS) that damage biological molecules[16]. Furthermore, other studies by Kimyon et al.[26] showed that the mechanism of action of prodigiosin is a nonspecific mechanism of procaryotes that involves RNA and DNA fragmentation, ROS generation, and expression of protein with caspase-like substrate specificity in bacterial cells. and activation of the programmed cell death[16],[26].

Moreover, prodigiosin can be used in certain textile applications, particularly in hospitals to reduce nosocomial infections. A recent study showed that this attractive color pigment, which was extracted from Serratia rubidaea RAM-Alex and used for dyeing various textile fabrics, had both good dyeing performance and antibacterial activity against Escherichia coli ATCC8739 and Staphylococcus aureus ATCC25923 strains[27].

MIC and minimum bactericidal concentration values of prodigiosin against some Gram-positive and Gram-negative bacteria are represented in [Table 2].{Table 2}

6.1.2. Antifungal activity

The prodigiosin pigment is also renowned for its antifungal activity against several fungal strains. Suryawanshi et al. demonstrated that prodigiosin inhibited the growth of fungal strains Fusarium oxysporum, Aspergillus flavus, and Penicillium notatum with MICs of 8, 10, and 21 μg/mL, respectively[28]. Other studies have demonstrated the antifungal activity of prodigiosin against several fungal strains including Epidermophyton floccosum (MIC = 41.5 μg/mL), Trichophyton spp. (MIC = 5.8-13.5 μg/mL), Microsporum spp. (MIC = 2.0-5.6 μg/mL)[29], Botrytis cinerea (MIC = 100 μg/mL)[30] and Didymella applanata (IC50 = 0.8 μg/mL)[31]. Recently, inhibition of the human fungal pathogen Mucor irregularis was reported by Hazarika et al. where prodigiosin, produced by the S. marcescens D1, induced increasing permeability in fungal cell membrane that helps the bacterium to invade fungal hyphae[32].

6.2. Antimalarial activity

Prodigiosin is characterized by its antimalarial activity, which was firstly studied by Castro in 1967. Papireddy et al. studied the antimalarial activity of the pigments prodigiosin and undecylprodigiosin which showed interesting activities against Plasmodium falciparum (P. falciparum) with IC50 of 8 and 7.7 nM, respectively[33]. P. falciparum was also sensitive to the action of metacycloprodigiosin with an IC50 of 12 nM[34]. Newly synthesized prodigiosin derivatives exhibited asexual blood-stage antiplasmodial activity at low nanomolar concentration against a panel of P. falciparum parasites[35].

6.3. Antiparasitic activity

Prodigiosin pigment is also recognized for its antiparasitic activities. The effects of prodigiosin against several parasites Entamoeba histolytica, Giardia lamblia, Naegleria fowleri, Acanthamoeba castellanii, Balamuthia mandrillaris (trophozoites), Balamuthia mandrillaris (cysts), Cryptosporidium parvum, Schistosoma mansoni, and Trypanosoma brucei were observed with IC50 values of 0.7, 3.8, 6.4, 2.2, 4, 3.8, 0.09, 1 and 0.03 μM, respectively[36]. Another study reported by Rahul et al. showed that prodigiosin, produced by Serratia nematodiphila, inhibited the growth of Trypanosoma brucei gambiense and P. falciparum, with IC50 values of 0.158 and 1.1 μg/mL, respectively[37]. Moreover, prodigiosin PG 3, produced by S. marcescens 2170, exhibited strong antiparasitic activity against Trypanosoma cruzi (souche CL, clone B5) with an IC50 of 0.6 μM in comparison with the current drug benznidazole with an IC50 of 18.9 μM[38]. Additionally, prodigiosin treatment led to severe membrane damage in Trypanosoma cruzi epimastigotes, accompanied by a change in parasite cell height and the surface roughness[38].

6.4. Insecticidal activity

Several studies demonstrated the efficacy of prodigiosin as an insecticidal pigment[39],[40],[41]. Sree et al. reported insecticidal activity and confirmed the efficacy of prodigiosin to kill various household pests. Indeed, total death of Periplaneta americana (Cockroaches) and Solenopsis geminata (tropical ants) was observed after treatment with prodigiosin, while 71%-85% mortality was observed against Dorymyrmex insanus (pyramid ants) and Isoptera (termites)[42].

6.5. Antioxidant activity

The antioxidant activity of prodigiosin was evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-azino- bis 3-ethylbenzthiazoline-6-sulfonic acid (ABTS) assays. The IC50 values recorded for DPPH and ABTS assays were 235 and 115 μg/mL, respectively in comparison to alpha-tocopherol with IC50 values of 24.3 and 12.7, respectively[43]. On the other hand, Arivizhivendhan et al. studied the antioxidant potential of prodigiosin, which was examined by DPPH and ABTS radical scavenging assays. Antioxidant activity was assessed via UV-visible, electron spin resonance, cyclic voltammetry, and excitation-emission spectra. The DPPH and ABTS radicals were completely scavenged by prodigiosin at the concentration of 10 mg/L[44].

6.6. Anticancer activity

Cancer is a global scourge. According to the World Health Organization, there were 19 million newly diagnosed cancer cases and 10 million cancer-related deaths globally in 2020. Cancer tends to be the leading cause of death in Western countries. It is a serious disease that can occur in any organ and at any age. Due to its severity, cancer causes profound anxiety and fear in most people. In view of this awareness, it is, therefore, necessary to find new anti- tumor agents that ideally have specific targets in the affected cells. Boger et al. demonstrated the anticancer effects of prodiginins[45]. Their results showed that prodigiosin has a significant in vitro cytotoxic effect on leukemic embryonic stem cells (IC50 = 3.7 × 10-4 μg/mL). Subsequent studies have demonstrated the effect of prodiginins on human leukemia cells (IC50 = 0.11 pM)[46], colon cancer (IC50 = 0.27 μM)[47], breast cancer (IC50 = 2.1 μM)[48], and hepatocellular carcinoma (IC50 = 0.27-0.59 μM)[49]. Many researches also focused on other tumor cell lines such as gastric cancer[50], hematopoietic cancer[51], and lung cancer[52]. Although the molecular targets of prodigiosin are not clearly defined, prodigiosin can target various signaling pathways that induce double-stranded DNA breaks and/or neutralize pH gradients, leading to changes in the cell cycle[53]. Another possible mechanism of prodigiosin action against cancer cells is the inhibition of protein phosphatase activity[54]. In 2016, Wang et al. reported that prodigiosin and its analogue obatoclax block Wnt signaling at nanomolar concentrations by preventing the Dishevelled phosphorylation. Cyclin D is an established target of Wnt signaling, and elevated cyclin D levels are a characteristic of advanced breast cancer. In a Wnt-driven murine transgenic model of breast cancer, prodigiosin decreased the levels of cyclin D and inhibited tumor growth[55]. In another study, it has been demonstrated that prodigiosin could induce apoptosis in HeLa cells. Apoptosis may be associated with the upregulation of Bax and caspase 3, the concomitant downregulation of Bcl-2 levels, and the activation of the extrinsic apoptotic signaling pathway[56]. These results provide a rationale for the introduction of prodigiosin analogues in advanced breast cancer clinical trials[55].

6.7. Anti-inflammatory activity

Cyclooxygenases (COX) or prostaglandin-endoperoxide synthases are the key enzymes in the synthesis of prostaglandins, the main mediator of inflammation, pain, and increased body temperature (hyperpyrexia). The body produces two forms of COX protein, COX1, and COX2. COX1 is involved in pain, blood clots, and stomach protection[57], whereas COX-2 is involved in pain by inflammation and plays a major role in prostaglandin biosynthesis in inflammatory cells and the central nervous systems[58]. The in silico anti-inflammatory activity of prodigiosin has been proven. Using molecular docking, the prodigiosin ligand revealed the highest fitness, score in comparison with the standard drug rofecoxib, suggesting that it may be an effective COX-2 inhibitor[59].

 7. Large-scale production of prodigiosin

Several biological activities have been reported for prodigiosin such as antibacterial, antifungal, antiparasitic, insecticidal, anticancer, antioxidant, and anti-inflammatory activities. This product is gaining more and more attention for its wide application in several medical, cosmetic, environmental, and food fields. Han et al. emphasize the importance of producing this pigment at a large scale while minimizing production costs[60].

Recently, several studies have been devoted to the optimization of prodigiosin production through the optimization of culture conditions, medium composition, and fermentation methods. The composition of the medium plays a critical role in the production of prodigiosin. In some studies, researchers have found that yeast extract or peptone and sucrose are important nitrogen and carbon sources for the production of prodigiosin by the S. marcescens strain[61],[62],[63]. On the other hand, glycerol has been proven by some researchers as an important source of carbon promoting better production of prodigiosin[64].

The prodigiosin synthesis pathway requires the amino acids proline, serine, and methionine as synthesis precursors. Adding these amino acids can stimulate the synthesis of the MBC precursor and enhance the production of the prodigiosin pigment[65].

In addition, the other precursor of prodigiosin 2-octenal, which is the initiator of MAP synthesis, is obtained essentially from the oxidation of fatty acids. Subsequently, the addition of oils such as olive oil[66], sunflower oil[67], palm oil[68], and peanut powder[69] could improve the production of prodigiosin. Several studies have been devoted to the search for low-cost substrates to minimize the cost of prodigiosin production, including kitchen waste[70], squid pen powder[41], and a-chitin from shrimp shells[71].

The production yield of prodigiosin is also affected by cultural conditions such as pH, temperature[63], oxygen levels[72], agitation[73], illumination[74], and the presence of salts[75]. Large- scale production of prodigiosin is achieved through the fermentation process. All biological, physical, and chemical conditions must be present to maximize production yield. The fermentation process for prodigiosin production has been studied using liquid and solid fermentation cultures[76],[77], foam flotation method for continuous fermentation[78], and immobilized culture[79].

 8. Prospects and conclusion

The synthesis of secondary metabolites by microorganisms in response to environmental stress is an important source of bioactive molecules. Indeed, secondary metabolites can serve as bioactive molecules in a variety of industries including medicine, food, or environmental fields. Biopigment prodigiosin is useful for numerous applications in a wide range of fields. The mechanism of prodigiosin synthesis is complex and involves many genes. It is regulated by quorum sensing system within the species S. marcescens and even with other microorganisms.

Studies are being conducted to lower the costs of prodigiosin production on a large scale through the use of economic media and to develop innovative downstream processing strategies for this compound. Moreover, the pharmacodynamic, pharmacokinetic and toxic information of prodigiosin in animals needs further investigation. Current works are also oriented towards the development of new prodigiosin derivatives which will certainly display more potent activity than the parent compound.

Conflict of interest statement

The authors declare that they have no competing interests.


The Tunisian ministry of higher education and scientific research is acknowledged.

Authors’ contributions

SM and MJ were responsible for writing and original draft preparation, BB and SA reviewed and edited the manuscript. All authors read and approved the final manuscript.


1Gulani C, Bhattacharya S, Das A. Assessment of process parameters influencing the enhanced production of prodigiosin from Serratia marcescens and evaluation of its antimicrobial, antioxidant and dyeing potentials. Malays J Microbiol 2012; 8(2): 116-122.
2Choi SY, Lim S, Yoon K, Lee JI, Mitchell RJ. Biotechnological activities and applications of bacterial pigments violacein and prodigiosin. J Biol Eng 2021; 15: 10. Doi: 10.1186/s13036-021-00262-9.
3Suryawanshi RK, Patil CD, Borase HP, Salunke BK, Patil SV. Studies on production and biological potential of prodigiosin by Serratia marcescens. Appl Biochem Biotechnol 2014; 173(5): 1209-1221.
4Rosenberg M, Blumberger Y, Judes H, Bar-Ness R, Rubinstein E, Mazor Y. Cell surface hydrophobicity of pigmented and nonpigmented clinical Serratia marcescens strains. Infect Immun 1986; 51(3): 932-935.
5Elahian F, Moghimi B, Dinmohammadi F, Ghamghami M, Hamidi M, Mirzaei SA. The anticancer agent prodigiosin is not a multidrug resistance protein substrate. DNA Cell Biol 2013; 32(3): 90-97.
6Danevcic T, Boric Vezjak M, Tabor M, Zorec M, Stopar D. Prodigiosin induces autolysins in actively grown Bacillus subtilis cells. Front Microbiol 2016; 7: 27.
7Kim D, Park YK, Lee JS, Kim JF, Jeong H, Kim BS, et al. Analysis of a prodigiosin biosynthetic gene cluster from the marine bacterium Hahella chejuensis KCTC 2396. J Microbiol Biotechnol 2006; 16(12): 1912-1918.
8Ramesh C, Vinithkumar NV, Kirubagaran R, Venil CK, Dufossé L. Applications of prodigiosin extracted from marine red pigmented bacteria Zooshikella sp. and Actinomycete Streptomyces sp. Microorganisms 2020; 8(4): 556.
9Do HNA, Nguyen THK. Studies on the prodigiosin production from Streptomyces coelicolor in liquid media by using heated Lactobacillus rhamnosus. J Appl Pharm Sci 2014; 4(5): 21-24.
10Kawasaki T, Sakurai F, Hayakawa Y. A prodigiosin from the roseophilin producer Streptomyces griseoviridis. J Nat Prod 2008; 71(7): 1265-1267.
11Darshan N, Manonmani HK. Prodigiosin and its potential applications. J Food Sci Technol 2015; 52(9): 5393-5407.
12Siva R, Subha K, Bhakta-Guha D, Ghosh AR, Babu S. Characterization and enhanced production of prodigiosin from the spoiled coconut. Appl Biochem Biotechnol 2011; 166(1): 187-196.
13Chauhan R, Choudhuri A, Abraham J. Evaluation of antimicrobial, cytotoxicity, and dyeing properties of prodigiosin produced by Serratia marcescens strain JAR8. Asian J Pharm Clin Res 2017; 10(8): 279-283.
14Katz DS, Sobieski RJ. Production of pigment precursors in Serratia marcescens at elevated temperatures. Trans Kans Acad Sci Kans Acad Sci 1980; 83(2): 91-94.
15Harris AKP, Williamson NR, Slater H, Cox A, Abbasi S, Foulds I, et al. The Serratia gene cluster encoding biosynthesis of the red antibiotic, prodigiosin, shows species- and strain-dependent genome context variation. Microbiology 2004; 150(11): 3547-3560.
16Yip CH, Yarkoni O, Ajioka J, Wan KL, Nathan S. Recent advancements in high-level synthesis of the promising clinical drug, prodigiosin. Appl Microbiol Biotechnol 2019; 103(4): 1667-1680.
17Fineran PC, Slater H, Everson L, Hughes K, Salmond GPC. Biosynthesis of tripyrrole and beta-lactam secondary metabolites in Serratia: Integration of quorum sensing with multiple new regulatory components in the control of prodigiosin and carbapenem antibiotic production. Mol Microbiol 2005; 56(6): 1495-1517.
18Williamson NR, Simonsen HT, Ahmed RAA, Goldet G, Slater H, Woodley L, et al. Biosynthesis of the red antibiotic, prodigiosin, in Serratia: Identification of a novel 2-methyl-3-n-amyl-pyrrole (MAP) assembly pathway, definition of the terminal condensing enzyme, and implications for undecylprodigiosin biosynthesis in Streptomyces. Mol Microbiol 2005; 56(4): 971-989.
19Thomson NR, Crow MA, McGowan SJ, Cox A, Salmond GPC. Biosynthesis of carbapenem antibiotic and prodigiosin pigment in Serratia is under quorum sensing control. Mol Microbiol 2000; 36(3): 539-556.
20Horng YT, Deng SC, Daykin M, Soo PC, Wei JR, Luh KT, et al. The LuxR family protein SpnR functions as a negative regulator of N-acylhomoserine lactone-dependent quorum sensing in Serratia marcescens. Mol Microbiol 2002; 45(6): 1655-1671.
21Slater H, Crow M, Everson L, Salmond GPC. Phosphate availability regulates biosynthesis of two antibiotics, prodigiosin and carbapenem, in Serratia via both quorum-sensing-dependent and -independent pathways. Mol Microbiol 2003; 47(2): 303-320.
22Darshan N, Manonmani HK. Prodigiosin inhibits motility and activates bacterial cell death revealing molecular biomarkers of programmed cell death. AMB Express 2016; 6: 50.
23Yip CH, Mahalingam S, Wan KL, Nathan S. Prodigiosin inhibits bacterial growth and virulence factors as a potential physiological response to interspecies competition. PLoS One 2021; 16(6): e0253445.
24Feng J, Shi W, Zhang S, Zhang Y. Identification of new compounds with high activity against stationary phase Borrelia burgdorferi from the NCI compound collection. Emerg Microbes Infect 2015; 4(6): e31.
25Hage-Hülsmann J, Grünberger A, Thies S, Santiago-Schübel B, Klein AS, Pietruszka J, et al. Natural biocide cocktails: Combinatorial antibiotic effects of prodigiosin and biosurfactants. PLOS One 2018; 13(7): e0200940.
26Kimyon Ö, Das T, Ibugo AI, Kutty SK, Ho KK, Tebben J, et al. Serratia secondary metabolite prodigiosin inhibits Pseudomonas aeruginosa biofilm development by producing reactive oxygen species that damage biological molecules. Front Microbiol 2016; 7: 972.
27Metwally RA, El Sikaily A, El-Sersy NA, Ghozlan HA, Sabry SA. Antimicrobial activity of textile fabrics dyed with prodigiosin pigment extracted from marine Serratia rubidaea RAM_Alex bacteria. Egypt J Aquat Res 2021; 47(3): 301-305.
28Suryawanshi RK, Patil CD, Koli SH, Hallsworth JE, Patil SV. Antimicrobial activity of prodigiosin is attributable to plasma-membrane damage. Nat Prod Res 2016; 31(5): 572-577.
29El-Bondkly AMA, El-Gendy MMA, Bassyouni RH. Overproduction and biological activity of prodigiosin-like pigments from recombinant fusant of endophytic marine Streptomyces species. Antonie Van Leeuwenhoek 2012; 102(4): 719-934.
30Someya N, Nakajima M, Hirayae K, Hibi T, Akutsu K. Synergistic antifungal activity of chitinolytic enzymes and prodigiosin produced by biocontrol bacterium, Serratia marcescens Strain B2 against gray mold pathogen, Botrytis cinerea. J Gen Plant Pathol 2001; 67: 312-317.
31Duzhak AB, Panfilova ZI, Duzhak TG, Vasyunina EA, Shternshis MV. Role of prodigiosin and chitinases in antagonistic activity of the bacterium Serratia marcescens against the fungus Didymella applanata. Biochem Biokhimiia 2012; 77(8): 910-916.
32Hazarika DJ, Kakoti M, Kalita R, Gautom T, Goswami G, Barooah M, et al. Prodigiosin from an endofungal bacterium Serratia marcescens D1 inhibits biofilm formation in Gram-positive bacteria. Microbiology 2021; 90(6): 829-838.
33Papireddy K, Smilkstein M, Kelly JX, Shweta A, Salem SM, Alhamadsheh M, et al. Antimalarial activity of natural and synthetic prodiginines. J Med Chem 2011; 54(15): 5296-5306.
34Isaka M, Jaturapat A, Kramyu J, Tanticharoen M, Thebtaranonth Y. Potent in vitro antimalarial activity of metacycloprodigiosin isolated from Streptomyces spectabilis BCC 4785. Antimicrob Agents Chemother 2002; 46(4): 1112-1113.
35Kancharla P, Li Y, Yeluguri M, Dodean RA, Reynolds KA, Kelly JX. Total synthesis and antimalarial activity of 2-(p-hydroxybenzyl)- prodigiosins, isoheptylprodigiosin, and geometric isomers of tambjamine MYP1 isolated from marine bacteria. J Med Chem 2021; 64: 8739-8754.
36Ehrenkaufer G, Li P, Stebbins EE, Kangussu-Marcolino MM, Debnath A, White CV, et al. Identification of anisomycin, prodigiosin and obatoclax as compounds with broad-spectrum anti-parasitic activity. PLoS Negl Trop Dis 2020; 14(3): e0008150.
37Rahul S, Chandrashekhar P, Hemant B, Bipinchandra S, Mouray E, Grellier P, et al. In vitro antiparasitic activity of microbial pigments and their combination with phytosynthesized metal nanoparticles. Parasitol Int 2015; 64(5): 353-356.
38Herráez R, Mur A, Merlos A, Viñas M, Vinuesa T. Using prodigiosin against some Gram-positive and Gram-negative bacteria and Trypanosoma cruzi. J Venom Anim Toxins Trop Dis 2019; 25: e20190001.
39Wang SL, Wang CY, Yen YH, Liang TW, Chen SY, Chen CH. Enhanced production of insecticidal prodigiosin from Serratia marcescens TKU011 in media containing squid pen. Process Biochem 2012; 47(11): 1684-1690.
40Patil NG, Kadam M, Patil VR, Chincholkar SB. Insecticidal properties of water diffusible prodigiosin produced by Serratia nematodiphila 213c. Curr Trends Biotechnol Pharm 2013; 7(3): 773-781.
41Liang TW, Chen SY, Chen YC, Chen CH, Yen YH, Wang SL. Enhancement of prodigiosin production by Serratia marcescens TKU011 and its insecticidal activity relative to food colorants. J Food Sci 2013; 78(11): M1743-M1751.
42Sree B, Sagar V, Deepak B, Tejaswini G, Yamarthi A, Jonnalgadda S. Evaluation of Prodigiosin pigment for antimicrobial and insecticidal activities on selected bacterial pathogens & household pests. Int J Sci Res 2019; 6(1): 96-102.
43Nguyen TH, Wang SL, Nguyen DN, Nguyen AD, Nguyen TH, Doan MD, et al. Bioprocessing of marine chitinous wastes for the production of bioactive prodigiosin. Molecules 2021; 26(11): 3138.
44Arivizhivendhan KV, Mahesh M, Boopathy R, Swarnalatha S, Regina Mary R, Sekaran G. Antioxidant and antimicrobial activity of bioactive prodigiosin produces from Serratia marcescens using agricultural waste as a substrate. J Food Sci Technol 2018; 55(7): 2661-2670.
45Boger DL, Patel M. Total synthesis of prodigiosin, prodigiosene, and desmethoxyprodigiosin: Diels-Alder reactions of heterocyclic azadienes and development of an effective palladium( II )-promoted 2,2’-bipyrrole coupling procedure. J Org Chem 1988; 53(7): 1405-1415.
46Campàs C, Dalmau M, Montaner B, Barragán M, Bellosillo B, Colomer D, et al. Prodigiosin induces apoptosis of B and T cells from B-cell chronic lymphocytic leukemia. Leukemia 2003; 17(4): 746-750.
47Montaner B, Pérez-Tomás R. Prodigiosin-induced apoptosis in human colon cancer cells. Life Sci 2001; 68(17): 2025-2036.
48Anwar MM, Shalaby M, Embaby AM, Saeed H, Agwa MM, Hussein A. Prodigiosin/PU-H71 as a novel potential combined therapy for triple negative breast cancer (TNBC): Preclinical insights. Sci Rep 2020; 10(1): 14706.
49Yamamoto C, Takemoto H, Kuno K, Yamamoto D, Tsubura A, Kamata K, et al. Cycloprodigiosin hydrochloride, a new H(+)/Cl(-) symporter, induces apoptosis in human and rat hepatocellular cancer cell lines in vitro and inhibits the growth of hepatocellular carcinoma xenografts in nude mice. Hepatol Baltim Md 1999; 30(4): 894-902.
50Díaz-Ruiz C, Montaner B, Pérez-Tomás R. Prodigiosin induces cell death and morphological changes indicative of apoptosis in gastric cancer cell line HGT-1. Histol Histopathol 2001; 16(2): 415-421.
51Montaner B, Navarro S, Piqué M, Vilaseca M, Martinell M, Giralt E, et al. Prodigiosin from the supernatant of Serratia marcescens induces apoptosis in haematopoietic cancer cell lines. Br J Pharmacol 2000; 131(3): 585-593.
52Chiu WJ, Lin SR, Chen YH, Tsai MJ, Leong MK, Weng CF. Prodigiosin- emerged PI3K/Beclin-1-independent pathway elicits autophagic cell death in doxorubicin-sensitive and -resistant lung cancer. J Clin Med 2018; 7(10): 321.
53Pandey R, Chander R, Sainis KB. Prodigiosins as anti cancer agents: Living upto their name. Curr Pharm Des 2009; 15(7): 732-741.
54Fürstner A, Reinecke K, Prinz H, Waldmann H. The core structures of roseophilin and the prodigiosin alkaloids define a new class of protein tyrosine phosphatase inhibitors. Chembiochem Eur J Chem Biol 2004; 5(11): 1575-1579.
55Wang Z, Li B, Zhou L, Yu S, Su Z, Song J, et al. Prodigiosin inhibits Wnt/β-catenin signaling and exerts anticancer activity in breast cancer cells. Proc Natl Acad Sci U S A 2016; 113(46): 13150-13155.
56Lin PB, Shen J, Ou PY, Liu LY, Chen ZY, Chu FJ, et al. Prodigiosin isolated from Serratia marcescens in the Periplaneta americana gut and its apoptosis-inducing activity in HeLa cells. Oncol Rep 2019; 41(6): 3377-3385.
57Watson DJ, Harper SE, Zhao PL, Quan H, Bolognese JA, Simon TJ. Gastrointestinal tolerability of the selective cyclooxygenase-2 (COX- 2) inhibitor rofecoxib compared with nonselective COX-1 and COX-2 inhibitors in osteoarthritis. Arch Intern Med 2000; 160(19): 2998-3003.
58Chhajed SS, Hiwanj PB, Bastikar VA, Upasani CD, Udavant PB, Dhake AS, et al. Structure based design and in-silico molecular docking analysis of some novel benzimidazoles. Int J Chem Tech Res 2010; 2(2): 1135-1140.
59Krishna PS, Vani K, Prasad MR, Samatha B, Bindu NS, Charya MAS, et al. In–silico molecular docking analysis of prodigiosin and cycloprodigiosin as COX-2 inhibitors. SpringerPlus 2013; 2: 172.
60Han R, Xiang R, Li J, Wang F, Wang C. High-level production of microbial prodigiosin: A review. J Basic Microbiol 2021; 61(6): 506-523.
61Zang CZ, Yeh CW, Chang WF, Lin CC, Kan SC, Shieh CJ, et al. Identification and enhanced production of prodigiosin isoform pigment from Serratia marcescens N10612. J Taiwan Inst Chem Eng 2014; 45(4): 1133-1139.
62Bhagwat A, Padalia U. Optimization of prodigiosin biosynthesis by Serratia marcescens using unconventional bioresources. J Genet Eng Biotechnol 2020; 18: 26. Doi: 10.1186/s43141-020-00045-7.
63Jardak M, Atoissi A, Msalbi D, Atoui D, Bouizgarne B, Rigane G, et al. Antibacterial, antibiofilm and cytotoxic properties of prodigiosin produced by a newly isolated Serratia sp. C6LB from a milk collection center. Microb Pathog 2022; 164: 105449.
64Elkenawy NM, Yassin AS, Elhifnawy HN, Amin MA. Optimization of prodigiosin production by Serratia marcescens using crude glycerol and enhancing production using gamma radiation. Biotechnol Rep 2017; 14: 47-53.
65Wei YH, Yu WJ, Chen WC. Enhanced undecylprodigiosin production from Serratia marcescens SS-1 by medium formulation and amino-acid supplementation. J Biosci Bioeng 2005; 100(4): 466-471.
66Lin C, Jia X, Fang Y, Chen L, Zhang H, Lin R, et al. Enhanced production of prodigiosin by Serratia marcescens FZSF02 in the form of pigment pellets. Electron J Biotechnol 2019; 40: 58-64.
67Luti K, Younis R, Mahmoud S. An application of solid state fermentation and elicitation with some microbial cells for the enhancement of prodigiosin production by Serratia marcescens. J Al-Nahrain Univ Sci 2018; 21(2): 98-105.
68Abdul Manas NH, Chong LY, Tesfamariam YM, Zulkharnain A, Mahmud H, Abang Mahmod DS, et al. Effects of oil substrate supplementation on production of prodigiosin by Serratia nematodiphila for dye-sensitized solar cell. J Biotechnol 2020; 317: 16-26.
69Picha P, Kale D, Dave I, Pardeshi S. Comparative studies on prodigiosin production by Serratia marcescens using various crude fatty acid sources- Its characterization and applications. Int J Curr Microbiol App Sci 2015; 2: 254-267.
70Xia S, Veony E, Yang Q. Kitchen waste as a novel available substrate for prodigiosin production by Serratia marcescens. IOP Conf Ser Earth Environ Sci 2018; 171(1): 012037.
71Nguyen VB, Chen SP, Nguyen TH, Nguyen MT, Tran TTT, Doan CT, et al. Novel efficient bioprocessing of marine chitins into active anticancer prodigiosin. Mar Drugs 2019; 18(1): 15.
72Sun D, Zhou X, Liu C, Zhu J, Ru Y, Liu W, et al. Fnr negatively regulates prodigiosin synthesis in Serratia sp. ATCC 39006 during aerobic fermentation. Front Microbiol 2021; 12: 734854.
73Mohammed SJ, Luti KJK. A kinetic model for prodigiosin production by Serratia marcescens as a bio-colorant in bioreactor. AIP Conf Proc 2020; 2213(1): 020027.
74Ryazantseva IN, Saakov VS, Andreyeva IN, Ogorodnikova TI, Zuev YF. Response of pigmented Serratia marcescens to the illumination. J Photochem Photobiol B 2012; 106: 18-23.
75Yamazaki G, Nishimura S, Ishida A, Kanagasabhapathy M, Zhou X, Nagata S, et al. Effect of salt stress on pigment production of Serratia rubidaea N-1: A potential indicator strain for screening quorum sensing inhibitors from marine microbes. J Gen Appl Microbiol 2006; 52(2): 113-117.
76de Araújo HWC, Fukushima K, Takaki GMC. Prodigiosin production by Serratia marcescens UCP 1549 using renewable-resources as a low cost substrate. Mol Basel Switz 2010; 15(10): 6931-6940.
77Arivizhivendhan KV, Mahesh M, Regina Mary R, Sekaran G. Bioactive prodigiosin isolated from Serratia marcescens using solid state fermenter and its bactericidal activity compared with conventional antibiotics. J Microb Biochem Technol 2015; 7(5): 305-312.
78Fu Q, Xiao Y, Duan X, Huang H, Zhuang Z, Shen J, et al. Continuous fermentation of a prodigiosin-producing Serratia marcescens strain isolated from soil. Adv Biosci Biotechnol 2019; 10(4): 98-108.
79Chen WC, Yu WJ, Chang CC, Chang JS, Huang SH, Chang CH, et al. Enhancing production of prodigiosin from Serratia marcescens C3 by statistical experimental design and porous carrier addition strategy. Biochem Eng J 2013; 78: 93-100.
80Lapenda JC, Silva PA, Vicalvi MC, Sena KXFR, Nascimento SC. Antimicrobial activity of prodigiosin isolated from Serratia marcescens UFPEDA 398. World J Microbiol Biotechnol 2015; 31(2): 399-406.
81Gohil N, Bhattacharjee G, Singh V. Synergistic bactericidal profiling of prodigiosin extracted from Serratia marcescens in combination with antibiotics against pathogenic bacteria. Microb Pathog 2020; 149: 104508.
82Priya KA, Satheesh S, Ashokkumar B, Varalakshmi P, Selvakumar G, Sivakumar N. Antifouling activity of prodigiosin from estuarine isolate of Serratia marcescens CMST 07. In: Velu RK (ed.) Microbiological research in agroecosystem management. 1st ed. India: Springer India; 2013, pp. 11-21.
83Clements T, Rautenbach M, Ndlovu T, Khan S, Khan W. A metabolomics and molecular networking approach to elucidate the structures of secondary metabolites produced by Serratia marcescens strains. Front Chem 2021; 9: 633870.