Encyclopedia
Please note this is a comparison between Version 1 by Rafael Gomes Araújo and Version 2 by Camila Xu.
Prodigiosin is characterized by having applications of great interest to the pharmacological industry. It has been shown in laboratory tests that prodigiosin has a good biological activity, such as antibacterial, antifungal, and antiviral.
- bionanocomposites
- prodigiosin
- pyrrolic compounds
1. Introduction
Prodigiosin is a natural red pigment that is obtained through a select group of Gram-negative bacteria of the Pseudomonas, Streptomyces, and Serratia genera. Only a few Gram-positive bacteria, such as Streptoverticillium rubrireticuli and Streptomyces longisporus, have been described with the ability to produce prodigiosin. It has been reported that a greater number of Gram-negative prodigiosin producing bacteria, compared to Gram-positive organisms, can be found in the literature, such as Pseudomonas magnesloruba, Vibrio psychroeryrhrous, Serratia rubidaea, Vibrio gazogenes, Alteromonas rubra, Rugamonas rubra, Serratia sp, and Serratia marcescens; the latter being the characteristic microorganism in pigment production, it has also been identified that both groups of bacteria produce prodigiosin as a secondary metabolite [1][2][3][4][5][6][7][8][14,15,16,17,18,19,20,21].
2. Biological Activity of Prodigiosin
Prodigiosin is characterized by having applications of great interest to the pharmacological industry. It has been shown in laboratory tests that prodigiosin has a good biological activity, such as antibacterial, antifungal, and antiviral. The benefit of having a bacterium with a secondary metabolite that has biological activity relies on the cost-effective production and the large amount of uses that this can have, not only in the pharmacological area but also in food preservatives, such as food coloring agents, among others.
2.1. Antimicrobial
This tripyrrole red pigment, has a notable antibacterial activity against Gram-negative bacteria such as Escherichia coli, Aeromonas hydrophila, Klebsiella pneumoniae, Proteus vulgaris, Proteus mirabilis, Pseudomonas aeruginosa, Salmonella enteritidis, and Salmonella Typhimurium [9][10][11][24,71,72], in addition to Gram-positive bacteria such as Staphylococcus aureus as well as its methicillin resistant strain, MRSA, Bacillus cereus, Corynebacterium glutamicum, Enterococcus faecalis, Enterococcus faecium, and Listeria monocytogenes [10][12][13][14][71,73,74,75]. Prodigiosin has also been observed to have a toxic effect on certain fungal species, such as Batrachochytrium dendrobatidis, B. salamandrivorans, Pythium myriotylum, Rhizoctonia solani, Sclerotium rolfsii, Phytophthora infestans, Fusarium oxysporum, and C. nymphaeae. The pigment’s antimycotic activity could be of use to control or to eradicate parasitic fungal species. The most common parameter for comparing antifungal activity was percentage inhibition, which is equal to the percentage difference in fungal cells with and without the pigment.2.2. Antioxidant
In the food industry, artificial additives are used to preserve food, which have shown deterioration in health due to their consumption, such as cell damage, inflammation, metabolic disorders, among others. Recently, an interest in natural preservative additives has been shown, given their benefit in human health. A balanced consumption of antioxidant compounds or foods rich in antioxidants allows for a reduction in oxidative stress and free radicals levels, generating protective effects in cells and balancing the immune system to produce defenses against various diseases, such as stress, cancer, hypertension, atherosclerosis, and gastrointestinal and hormonal disorders [15][16][17][18][80,81,82,83]. Prodigiosin has demonstrated high antioxidant potential with interest for many applications. The strong antioxidant activity may be attributed to conjugated double bond and ring pyrrole structures of prodigiosin [19][84]. A recent study demonstrated the high antioxidant activity of purified prodigiosin from Serratia marcescens, showing 92 and 99% of scavenging at 5 mg/mL of prodigiosin, for free radicals ABTS and DPPH, respectively. The antioxidant properties of prodigiosin also demonstrated benefits in the preservation of foods through the decrease of rancidity and microbiological contamination, increasing shelf life, and adding some additional properties, such as color for a pleasant appearance for the consumer [20][85]. Prodigiosin purified from radio-resistant Streptomyces sp. WMA-LM31 showed antioxidant activity for DPPH with a scavenging capacity of 62%, a protein oxidation inhibition of 54.8%, and a lipid peroxidation of 25.4% at 10 µg/mL, showing strong antioxidant activity at low concentrations [19][84]. Prodigiosin also showed strong activity against different free radicals, the ability to block the formation of superoxides, and the inhibition of Fenton reactions, reducing the negative effects of protein and lipid oxidation as well as the prevention of DNA damage [19][84]. Nguyen et al. produced prodigiosin from marine chitinous wastes by a bioprocess with S. marcescens strains, reporting a moderate antioxidant activity, with values of inhibition (IC50) of 115 and 235 µg/mL for ABTS and DPPH, respectively [18][83].2.3. Antitumoral
Cancer is a global health problem, representing one of the main causes of mortality worldwide and the first or second of premature mortality in the main countries of the world. According to the World Health Organization, in 2020 an estimated 19.3 million new cases and 10 million deaths were estimated in which each of 5 people in the world developed cancer during their lifetime and in which one in 11 women and one in 8 men died from cancer [21][22][86,87]. For 2070, a strong increase in the incidence of cancer is estimated, twice the current level, due to population growth and aging, demographic changes and an increase in risk factors for cancer development associated with demographic increase [23][88]. The main types of cancer with the highest incidence in 2020 are breast, prostate, lung, and colorectal cancers, and the cancers with the highest mortality rates were lung, colorectal, and liver, in order of appearance [24][89]. The uncontrolled increase in the incidence of cancer, high costs of treatment, and resistance to current drugs have created a great need to design, research, and discover new compounds. The search for natural compounds produced by different organisms has been the most important strategy, highlighting that more than half of the approved treatments against cancer are of natural origin or derivatives [25][90]. Prodigiosin has shown a high potential as an antitumoral agent against colorectal cancer, inhibiting late-stage autophagy and increasing sensitivity to 5-fluorouracil of different colorectal cancer cells (HCT116 and SW480) through blocking autophagosome–lysosome fusion and maturation of lysosomal cathepsin [26][92]. Ji et al. demonstrated that prodigiosin markedly decreases the proliferation of K562 cells (chronic myelogenous leukemia) through increased activity of caspases-3, -8, -9 and increased reactive oxygen species, resulting in the inhibition of autophagy and the induction of apoptosis [27][93]. Nguyen et al. demonstrated the strong anticancer effect of prodigiosin in different cancer cell lines, MCF-7, A549, HepG2 and WiDr, with inhibition values of 92.1%, 93.1%, 94%, and 92%, and low values of IC50, 0.102 µg/mL, 0.182 µg/mL, 0.161 µg/mL, and 0.441 µg/mL, respectively [28][94]. The purified prodigiosin bioproduced from marine chitin showed high anticancer activity against MCF-7, A549, and HepG2, and an efficacy of 2.75, 1.67, and 3.25 times greater than Mytomycin C, a commercial anticancer compound, respectively, proposing some mechanisms that prodigiosin affects, such as mitogen-activated protein kinase regulators, pH modulators, DNA cleavage agents, and cell cycle inhibitors [29][95]
An anticancer study demonstrated the effect of prodigiosin through tests with prostate cancer (PC3) and human choriocarcinoma (JEG3) cell lines in vitro and PC3 and JEG3 tumor-bearing nude mice in vivo, showing an inhibition of the proliferation and a reduction in the size and weight of the tumors, depending on the prodigiosin concentration and the treatment time, respectively [30][96]. Berning et al. demonstrated that prodigiosin increases the sensitivity of cisplatin-resistant and sensitive urothelial carcinoma cell lines (RT-112) to cisplatin mediated by dysregulation of lysosomal function and reduction of cathepsin B and L activity [31][23]. Prodigiosin has great cytotoxic activity against many melanoma cancers cells lines, such as NGM, 501-Mel, WM293A, HT-144, SK-Mel-19, SK-Mel-28, and SK-Mel-147, showing mean IC50 values of 0.2 µM through kinases modulation, intracellular acidification, DNA damage, and apoptosis induction [32][97]. Breast cancer is the type of cancer with the highest incidence worldwide and the second with the highest mortality rate. Prodigiosin has recently shown very relevant effects in the fight against this disease. In MDA-MB-231 (hormone-independent breast cancer cell line) and MDA-MB-468 cells, the prodigiosin at nanomolar concentrations, blocking the Wnt/β-catenin pathway, decreased phosphorylation of GSK3β, DVL2, and LRP6 and suppressed β-catenin–stimulated Wnt target gene expression [33][98].
A novel study of antitumoral activity of prodigiosin combined with PU-H71 against MDA-MB-231 showed high levels of caspases 3, 8, and 9 and decreased the levels of mTOR expression and HSP90α expression and transcription levels, which resulted in a breakthrough for a new therapy against triple negative breast cancer [34][99]. The high antitumor activity of prodigiosin at low concentrations and the low secondary effects against healthy cells has strengthened and intensified research into it as a new anticancer therapy. Obatoclax, a synthetic analog of prodigiosin, is being studied in phase I and II clinical trials for the treatment of lymphoma, myelodysplastic syndrome, and lung cancer [32][97].
2.4. Antiprotozoal
Natural compounds and their semisynthetic derivatives are the primary strategy for obtaining and developing new drugs for the treatment of parasitic diseases [35][109]. Malaria is a disease that threatens global health, as it has developed resistance to current drugs and is causing more than a million deaths annually. Prodigiosin and derivatives, such as undecylprodigiosin and metacycloprodigiosin in nanomolar concentrations and IC50 between 5–12 nM, were shown to exhibit potent in vitro antimalarial activity against Plasmodium falciparum, the parasite that causes malaria disease in humans [36][37][110,111]. Mosquitoes are the vectors for the transmission of deadly diseases, such as malaria and dengue. The control of the reproduction and spread of mosquitoes is an alternative for the control and reduction of new infections [38][112]. The larvicidal activity of prodigiosin has been reported, and it is known. Prodigiosin at a concentration of 100 ppm demonstrated a larvicidal activity against Aedes aegypti of 32% and 76% mortality with 24 and 48 h of incubation, respectively [39][113]. Purified prodigiosin has shown high larvicidal activity against larval and pupal stages of Aedes aegypti and Anopheles stephensi mosquitoes, obtaining IC50 values between 14 to 21 µg/mL and 19 to 32 µg/mL, respectively, in the various growth stages. The larvicidal concentration to both mosquitoes was found at 62.5 µg/mL for the three firsts growth stages [38][112].
