Prodigiosin: a promising biomolecule with many potential biomedical applications

Figures & data

Figure 1. Comparative chemical structure of prodigiosin and its different isoforms (with permission from [18]).

Table 1. Summary of PG production reported in the literature.

Strain	Methodology (volume)	Medium	Productivity (mg L^−1 h^−[^Citation1]) (Production/time)	Temperature (°C) – pH	References
Serratia spp. AM8887	Bioreactor (20 L)	6 g L^−1 Sucrose, 6 g L^−1, and glycerol, 15 g L^−1 NaCl, and 12 g L^−1 fertilizer waste	368.4 7,000 mg L^−1/19 h	25°C – 6.5	[32]
S. marcescens WT	Bioreactor (7 L)	Saline medium	10.9 600 mg L^−1/55 h	30°C – 6.0	[156]
S. marcescens UTM1	Bioreactor (5 L)	Brown sugar and lactose in nutrient broth	≈333.3 ≈8000 mg L^−1/24 h	25°C – 7.0	[50]
S. marcescens NPLR1	Bioreactor (2 L)	Saline suppl. with tannery fleshing	1,200 48,000 mg L^−1/40 h	30°C – 8.0	[157]
S. marcescens CF-53	Bioreactor (2 L)	Peanut oil cake extract	0.95 40 mg L^−1/42 h	30°C – 7.0	[158]
Serratia sp. KH-95	Bioreactor coupled with extraction system (1 L)	20 g L^−1 casein, 1 g L^−1 MgSO4⋅7H2O, 1 g L^−1 NaCl, and 1.7 g L^−1 K2HPO4	400 4,800 mg L^−1/12 h	28°C – 7.0	[159]
S. marcescens JX 1	Bioreactor (200 mL)	20 g L^−1 glycerol, 2.0 g L^−1 glycine, and 16.0 g L^−1 Peptone	135.4 6,500 mg L^−1/48 h	28°C – NR	[160]
S. marcescens WT	Bioreactor (100 mL)	1% M9 mineral suppl 1% Tannery fleshing	11.9 1,143 mg L^−1/96th	30°C – 6.8	[161]
S. marcescens WT	Solid state fermentation (1 Kg)	Saline medium supplemented with wheat bran + Tannery fleshing	2,963.7 mg kg^−1 h^−[^Citation1] 88,910 mg kg^−1/30 days	29°C – 6.8	[162]
S. marcescens UCP 1549	Solid-state fermentation (5 g)	Saline medium suppl with food wastes: sugarcane bagasse, instant noodle waste, wheat bran, tangerine peels, pineapple peels, and crown	998.3 mg kg^−1 h^−[^Citation1] 119,800 mg kg^−1/120 h	28°C – NR	[163]
S. marcescens subsp. lawsoniana	Vessel (500 mL)	5 g L^−1 maltose, 10 g L^−1 peptone, 5 g L^−1 NaCl, and 0.3 g L^−1 sodium acetate	9.1 656 mg L^−1/72 h	28°C – NR	[164]
S. marcescens MN5	Erlenmeyer (100 mL)	1% (v/v) of crude glycerol, or cotton seed cake, or soybean cake or 1% (w/v) black seed cake	333,3 48,000^#/144	22°C – 9.0 Ranges of pH/temps	[51]
S. marcescens NITDPER1	Erlenmeyer (100 mL)	Peanut oil and palm oil broth	73.8–89.3 4,430–5,360 mg L^−1/60 h	30°C – 7.0	[165]
S. marcescens SR1	Erlenmeyer (100 mL)	casein-enriched medium supplemented with 4% vegetable oil mixture (sunflower, coconut, and olive oil)	9.1 765.1 mg L^−1/84 h	30°C – 7.0	[166]
S. marcescens ATCC 13880	Erlenmeyer (100 mL)	Sucrose and commercial or sheep wool peptones	2.43–4.74 175–341 mg L^−1/72 h	25°C – 8.0	[167]
S. marcescens WT	Erlenmeyer (50 mL)	Powdered peanut seed broth	1,083 39,000 mg L^−1/ 36 h	28°C – 7.0 Dif temps	[168]
S. marcescens WT	Erlenmeyer (50 mL)	Sesame and peanut seed broth	343.8–783.3 16,500–37,600 mg L^−1 /48 h	28°C – 7.0 Dif temps	[169]
S. marcescens FZSF02	Erlenmeyer (50 mL)	Several combinations of carbon and nitrogen sources	4.9–214.2 353–15,420.9 mg L^−1/72 h	26°C – 7.0	[170]
S. marcescens TKU011	Erlenmeyer (50 mL)	Saline suppl. with 1.50% squid pen powder/1.0% chitin plus 0.6% casein	103.3–192.5 2,480–4,620 mg L^−1/24 h	25°C – 6.15 Ranges of pH/temps	[171]
S. marcescens TKU011	Erlenmeyer (50 mL)	Saline medium suppl with 0.5–2% powder of squid pen, shrimp head, crab shell, and shrimp shell	10.2 978 mg L^−1/96 h	30/25°C – 7.0 Ranges of temps	[172]
S. marcescens SS-1 SMΔR*	Erlenmeyer (50 mL)	10 g L^−1 tryptone, 5 g L^−1 yeast extract, 2–6% vegetable oils	5.25–7.90 525–790 mg L^−1/10 h	30°C – ≈9.0	[173]
S. marcescens MO-1	Erlenmeyer (50 mL)	1.00% mannitol, 0.40% yeast extract, and 0.40% ram horn peptone	5.8 278 mg L^−1/48 h	28°C – 7.0	[174]
S. marcescens BWL1001	Erlenmeyer (25 mL)	Saline suppl. with 100 g L^−1 soybean oil, 10 g L^−1 peptone,	768.1 27,650 mg L^−1/36 h	28°C – 5.0	[175]
S. marcescens S389	Sakaguchi flask (100 mL)	Saline medium suppl with 15% ethanol	41.7 3,000 mg L^−1/72 h	28°C – 6.8	[176]
S. marcescens WT	Erlenmeyer (20 mL)	Proline, peptone plus Kitchen wastewater	20.7 870 mg L^−1/42 h	28°C – 8.0	^[Citation177]
S. marcescens C3	Erlenmeyer immobilized cells on alginate (50 mL)	Saline suppl. with many Carbon and nitrogen sources	31.9–216.7 2,300 mg L^−1 to 15,600 mg L^−1/72 h	30°C – 6.0	[59]
S. marcescens WT	Erlenmeyer (NR)	Peanut seed broth, Sunflower seed broth/maltose, or glucose	31.8–33.2 1,525–1,595 mg L^−1/48 h	28°C – 6.0	[178]
S. marcescens SK4-72	Erlenmeyer (NR)	2% Sucrose, 1.5%, beef extract and 0.75% L-proline	144.7 15,630 mg L^−1/108 h	30°C – ≈9.0	[179]
S. marcescens WT	Erlenmeyer (NR)	Casein, Madhuca latifolia, powder, sweet potato, sesame, and nitrogen sources like casein, beef extract, urea	100 4,800 mg L^−1/ 48 h	28°C – 7.0 Ranges of pH/temps IMP	[180]
S. marcescens JNB 5–1	Erlenmeyer (NR)	Synthetic medium	60.7 5,830 mg L^−1/96 h	30°C – ≈9.0 Ranges of temps	[181]
S. marcescens JNB5-1	Erlenmeyer (NR)	2% Sucrose, 1.5%, beef extract and 0.75% L-proline	58.8 6,350 mg L^−1/108 h	30°C – ≈9.0	[179]
S. marcescens BMJ 816 and AMJ 817	Erlenmeyer (NR)	1.60% Starch, 1.60% peptone and 1.0% trace compounds,	2.6 103 mg L^−1/40 h	30°C – ≈9.0	[182]
S. marcescens UCP1549	Agar culture (20 mL)	2% mannitol medium suppl with 6% cassava waste	1,031 49,500 mg L^−1/48 h	28°C – 7.0	[183]
S. marcescens ATCC 13880	Agar culture (20 mL)	Peanut seed, mustard seed, and sesame seed oil cakes nutrient agar	12.5 900 mg L^−1/72 h	28°C – 7.5	[184]
Serratia nematodiphila YO1	Bioreactor (3.6 L)	Synthetic suppl. with vegetable oils	1.78–1.86 89.1–93.2 mg L^−1/50 h	26°C – 7.0 Ranges of pH/temps	[34]
Serratia nematodiphila RL2	Erlenmeyer (50 mL)	Maltose, corn steep liquor, yeast extract	12.8 640 mg L^−1/50 h	30°C – 6.0/7.0	[33]
Streptomyces sp. NRCF69*	Erlenmeyer (50 mL)	Saline medium suppl with 2.0% crushed peanut, sesame, or sunflower seeds, fenugreek, their oils, and coconut oil	391.7 47,000 mg L^−1/120 h	28°C – 7.3	[36]
Streptomyces sp. JS520	Erlenmeyer (150 mL)	Maltose soy-yeast extract	0.96 138 mg L^−1/144 h	30°C – 7.0 Ranges of pH/temps	[37]
Streptomyces coelicolor*	Agar plate	MS agar	0.90 96.8 mg g^−1 DW/108 h	30°C – 7.2	[38]
Achromobacter denitrificans SP1	Test tube (10 mL)	Saline medium suppl. with Di (2-ethylhexyl) phthalate	7.3 x10^−[^Citation4] ^– 5.48 0.175–1,314 mg L^−1/240 h	24°C – 8.8	[39]
S. rubidaea RAM_Alex	Erlenmeyer (25 mL)	5.0 g L^−1 beef extract, 7.0 g L^−1 peptone, 1.0 g L^−1 yeast extract, 10.0 g L^−1 NaCl	33.3 1,600 mg L^−1/48 h	30°C – 6.0	[35]
Hahella chuejuensis KCTC2396	Agar plates	Marine broth 2216	0.59 28.10 mg L^−1/48 h	30/37°C – 7.0	[40]
Zooshikella rubidus S1-1	Agar plates	Marine broth 2216	1.0 47.80 mg L^−1/48 h	30/37°C – 7.0	[40]

Notes: NR, No Reported; WT, wild type; *, mutants; ^#, estimated from Elkenawy et al., 2017 [51].

Figure 2. Schematic steps for Prodigiosin purification.

Table 2. Antibacterial activity of Prodigiosin.

Strain	Method	Concentration	Inhibition	Reference
S. aureus	Diffusion test	0.3 mg/disc	35.0 ± 0.6 mm	[70]
		0.15 mg/disc	60 mm	[71]
	MIC	5 µg/mL	–	[79]
	MBC	9 µg/mL	–	[73]
	Turbidity	0.18 µg/mL	30%	[11]
	CFU/mL	15% wt	97%	[144]
E. coli	Turbidity	100 µg/mL	30%	[11]
		0.64 mg/cm[^Citation3]	97.31%	[143]
		2 mg/mL*	55%	[135]
		120 µg/mL	40%	[185]
	Diffusion test	0.15 mg/disc	60 mm	[71]
	MIC	25 µg/mL	–	[79]
	MBC	20 µg/mL	–	[73]
B. cereus	Diffusion test	0.15 mg/disc	60 mm	[71]
	MBC	12 µg/mL	–	[73]
	Turbidity	0.64 mg/cm[^Citation3]	97.33%	[143]
		2 mg/mL*	40%	[135]
P. aeruginosa	MIC	15 µg/mL	–	[79]
	MBC	16 µg/mL	–	[73]
	CFU/mL	15% wt	98%	[144]
E. fecaelis	Diffusion test	0.3 mg/disc	22.0 ± 1.0 mm	[70]
S. pyogenes	Diffusion test	0.3 mg/disc	14.0 ± 0.6 mm	[70]
C. botulinum	Diffusion test	0.15 mg/disc	70 mm	[71]
S. enterica	Diffusion test	0.15 mg/disc	20 mm	[71]
V. vulnificus	Diffusion test	0.15 mg/disc	50 mm	[71]
B. subtilis	MIC	10 µg/mL	–	[79]
S. thypi	MIC	5 µg/mL	–	[79]

Table 3. Antifungal activity of Prodigiosin.

Strain	Method		Concentration	Inhibition (%)	Reference
F. oxysporium		MIC	8 µg mL^−1	–	[79]
A. flavus		MIC	10 µg mL^−1	–	[79]
P. notatum		MIC	22 µg mL^−1	–	[79]
Cladosporium		MIC	20 µg mL^−1	–	[79]
C. albicans		Turbidity	0.30 µg mL^−1	30	[11]
P. myriotylum		Diffusion test	ND/crude extract	71.33	[80]
R. solani		Diffusion test	ND/crude extract	61.33	[80]
S. rolfsii		Diffusion test	ND/crude extract	49.33	[80]
P. infestans	Diffusion test		ND/crude extract	48.66	[80]
F. oxysporum	Diffusion test		ND/crude extract	31	[80]
M. fijiensis	Germ tube growth		996 µg mL^−1	50	[81]
B. cinerea	Spore germination		10 µg mL^−1	72	[82]

Table 4. Anticancer activity of Prodigiosin.

Cancer type	Cell lines	Key findings	References
Gastric	HGT-1	− 4.0 µM PG decreased 80% cell viability, and induced DNA fragmentation and nuclear condensation	[186]
	BCRP EPG85- 257RDB	- IC50: 5–10 µM PG - PG is not an MDP protein substrate	[29]
Breast	KPL-1 MCF-7 MDA-MB-231 T-47D MKL-F	- IC50: 0-46 – 0.62 µM PG - 0.46 µM CycloPG induced G0/G1 cell cycle arrest and apoptosis in KPL-1 cells - Intracellular acidification was essential for the apoptosis	[97,187]
	MDA-MB-231 MDA-MB-468	- IC50: 0.06 − 0.26 µM PG (48 h) - PG induced caspase activation - PG suppressed MDA-MB-231 cell migration and invasion - PG inhibited tumor growth in an MDA-MB-231 xenograft mouse model - PG inhibited WNT/ β-Catenin signaling in breast cancer cells both in vitro and in vivo	[104]
	MCF-7 MDA-MB-231	- IC50: 1–2 µM PG - PG induced cyt C release, caspase activation, and PARP cleavage.	[98]
Lung	A549 (Dox-S) A549 (Dox-R)	- IC50: 10 µM for both cell lines - PG induced both autophagy and apoptosis	[103]
	GLC4	- IC50: 0.12–0.15 µM PG - PG induced cyt C release in cytosol	[99]
Colon	LD-1 c SW-620	− 1.1 µM PG induced DNA fragmentation and PARP cleavage (apoptotic markers)	[97,188]
Prostate	PC3	- PG (50 µg/mL) induced apoptosis through induction of p53 and Bax/Bcl-2 expression (mitochondrial pathway) - PG (100–250 µg/kg) inhibited tumor growth in PC3 tumor-bearing nude mice in vivo	[106]
Hematopoietic	Jurkat HL-60	- PG extract (10 µg/mL) induced apoptosis	[97,189]
Chronic lymphocytic leukemia	Patient-derived cells	− 0.1 µM PG inhibited 50% cell viability and promoted caspase activation	[97,190]
Neuroblastoma	SH-SY5Y LAN-1 IMR-32 SK-N-AS	- IC50: 0.7–7 µM PG - PG is a sequestering proton molecule that abolishes intracellular pH gradient, promoting ATP depletion - ATP depletion (starvation) leads to apoptosis	[100]

Figure 3. Obatoclax mesylate, a derivative of prodigiosin with high anticancer activity.

Table 5. Different drug delivery systems for prodigiosin vehiculation.

Delivery system	Design	EE (%)/DL*	Application	References
PG loaded Chitosan microspheres (40–60 μm)	w/o emulsion technique with glutaraldehyde as a cross-linker	67–90% / 7–45%	Human Breast cancer	[130]
PG loaded biodegradable (PLGA)-based microparticles (5–50 μm)	single emulsion solvent evaporation technique with (PVA) as an emulsifier	-	Human Breast cancer	[131]
PG-conjugated AgNPs (9.98 nm)	a rapid one-step method based on the amphoteric properties of silver oxide in alkaline solutions	-	Human Liver cancer	[132]
PG- conjugated biosynthesized gold nanoparticles (AuNPs) (51–60 nm)	A rapid method in presence of gold (III) chloride tri-hydrate, conjugated with LHRH peptide and addition of PG by physisorption	-	Human Breast cancer	[133]
Dendrigraft poly-L-lysines PG loaded nanoparticles (DGL/CSA-PNPs) (396.10 nm)	Synthetic placental chondroitin sulfate (CSA)-binding peptide (plCSA-BP) used to modify dendrigraft poly-L-lysines (DGL)	81–89% / 38–40%	Choriocarcinoma	[134]
β-Cyclodextrin grafted magnetic nanoparticles and carboxymethyl chitosan-coated magnetic nanoparticles (38.2–121.1 nm)	Two-step synthesis by co-precipitation of ferrous and ferric salts in a carboxymethylated β-Cyclodextrin. Single-step synthesis of chitosan-coated Fe3O4. PG loaded via inclusion complexation and adsorption	81–92% / 56–59 mg per 100 mg MNPs	Human Breast cancer/Human Liver cancer	[136]
PG nanomicelles (223.8/217.1 nm)	Microbial fermentation in presence of Tween 80	-	Antimicrobial against Staphylococcus aureus and Escherichia coli	[19,137]
κ-carrageenan and maltodextrin PG loaded microparticles (0.5–5 µm)	Spray-dried technique with κ-carrageenan and maltodextrin as encapsulation agents	-	Enhanced the natural pigment’s properties as a colorant	[138]
PG loaded P(NIPA)-based hydrogels, P(NIPA-co-AM), and P(NIPA-co-BMA)	P(NIPA)-based hydrogels were prepared by free-radical polymerization	-	Human Breast cancer	[141,142]
Hybrid composite nanofibers (1–1.4 μm)	Developed by electrospinning with PLGA, gelatin, pluronic F127, and PG	54%/ 3.60 mg mL^−1 of PLGA/Ge-F127/PG	Human Breast cancer	[145]
PDMS implantable packages (2–4 mm)	PDMS packages containing PG-storing hydrogel (PNIPA and co-monomers of AM and BMA)	-	Human Breast cancer	[146,147]

* EE (Encapsulation efficiency) / DL (Drug loading)

Figure 4. Schematic process of the prodigiosin nanomicelles production (modified from Gong et al.[18]).

Figure 5. SEM micrograph showing the morphologies of (a) PLGA/Ge-PG electrospun scaffold and (b) PLGA/Ge-F127/PG scaffold (with permission from [117]).

Figure 6. The potential application of 3D printing to design aortic root starting from the computed tomography cross-sectional view, followed by the 3D computational Model to finally obtain a 3D-Printed phantom (with permission from [121]).

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