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Prodigiosin as a high-valued compound, which is a microbial secondary metabolite, has the potential for antioxidant and anticancer effects. However, the large-scale production of functionally active Hahella chejuensis-derived prodigiosin by fermentation in a cost-effective manner has yet to be achieved. In the present study, we established carbon source-optimized medium conditions, as well as a procedure for producing prodigiosin by fermentation by culturing H. chejuensis using 10 L and 200 L bioreactors. Our results showed that prodigiosin productivity using 250 mL flasks was higher in the presence of glucose than other carbon sources, including mannose, sucrose, galactose, and fructose, and could be scaled up to 10 L and 200 L batches. Productivity in the glucose (2.5 g/L) culture while maintaining the medium at pH 6.89 during 10 days of cultivation in the 200 L bioreactor was measured and increased more than productivity in the basal culture medium in the absence of glucose. Prodigiosin production from 10 L and 200 L fermentation cultures of H. chejuensis was confirmed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) analyses for more accurate identification. Finally, the anticancer activity of crude extracted prodigiosin against human cancerous leukemia THP-1 cells was evaluated and confirmed at various concentrations. Conclusively, we demonstrate that culture conditions for H. chejuensis using a bioreactor with various parameters and ethanol-based extraction procedures were optimized to mass-produce the marine bacterium-derived high purity prodigiosin associated with anti-cancer activity.

We report two pyridyl-linked benzimidazolyl hydrazones as HCl cotransporters that are 5 and 2 times superior to prodigiosin, a natural product whose transport efficiency has never been routed by synthetic molecules. These hydrazones provide a suitable HCl binding site through a cooperative protonation and chloride ion recognition. HCl transport by the most active compound induces lysosome deacidification. Viability assays confirmed that the compounds induce cytotoxicity toward human breast cancer MCF-7 cells but are relatively nontoxic toward noncancerous HEK293T cells.

Prodigiosin, a secondary metabolite extracted from Serratia marcescens (S. marcescens), could induce apoptosis in various cancer cells, with however low toxicity on normal cells. The red pigment was extracted from a strain S. marcescens NJZT-1 isolated from soil, which had antibacterial activity. Spectral analyses (LC-ESI-MS, UV-VIS spectrophotometry, infrared spectra and HPLC) and TLC indicated the presence of prodigiosin in the extracellular bacterial culture extracts. The red pigment effectively killed the TSC2-null cells, whose mutation resulted in the progressive and systemic disease LAM. Our findings provide interesting evidence and important basis for the development of new therapeutic compounds with high potential effects against TSC2-null cells.

In this review, we discuss violacein and prodigiosin, two chromogenic bacterial secondary metabolites that have diverse biological activities. Although both compounds were “discovered” more than seven decades ago, interest into their biological applications has grown in the last two decades, particularly driven by their antimicrobial and anticancer properties. These topics will be discussed in the first half of this review. The latter half delves into the current efforts of groups to produce these two compounds. This includes in both their native bacterial hosts and heterogeneously in other bacterial hosts, including discussing some of the caveats related to the yields reported in the literature, and some of the synthetic biology techniques employed in this pursuit.

Objective The aim of this study is to investigate the role of prodigiosin on P. aeruginosa' s biofilm genes involved in the pathogenicity and persistency of the bacteria. Patients and methods Materials and methods: Gram negative bacterial isolates were taken from burn and wounds specimen obtained from some of Baghdad hospitals. Forty six isolates were identified as Pseudomonas aeruginosa and four isolates as Serratia marcescens by using biochemical tests and VITEK 2 compact system. Susceptibility test was performed for all P. aeruginosa isolates, the results showed that 100% were resistant to Amikacin and 98% were sensitive to Meropenem. Resistant isolates were tested for biofilm formation; the strong and moderate isolates (17) were detected by PCR for AlgD gene presence. From 17 isolates only two had AlgD gene. All serratia isolates were screened for prodigiosin production, which were extracted from the best producer isolate. Minimal inhibitory concentration was assessed for prodigiosin and ciprofloxacin and synergism between them against the two isolates of P. aeruginosa. Results Results and conclusions: The results showed that the synergistic effect decreased MIC of both prodigiosin and ciprofloxacin by combination, and reduction of biofilm formation was detected. RNA was extracted from the two selected isolates as control in addition to three treatments. The result of quantitative real time PCR showed down regulation in the AlgD gene expression level under some treatments, while there was no gene expression in most treatments with both sub-MICs treatment.

Background and purpose: Chronic myeloid leukemia (CML) as a myeloproliferative disease is characterized by increased cellularity of bone marrow. Implementing the latest treatment protocols is currently accompanied by serious and life-threatening side effects. There are worldwide attempts to find new effective and potent therapeutic agents with minimal side effects on CML patients. This in vitro study was carried out to discover the potential antiproliferative and apoptotic effects of naturally produced prodigiosin (PDG) on K562 cells as an accepted model of CML. Experimental approach: The anti-proliferative effect of PDG was measured by MTT assay. To highlight the mechanism of cytotoxicity, the apoptotic cell death pathway was investigated by morphological and biochemical assessments. The dual acridine orange/ethidium bromide staining technique and western blotting method were applied to assess the mechanism of the potential apoptotic impact of PDG on K562 cells. Findings/Results: PDG-induced time- and concentration-dependent anti-proliferative effects were revealed with an estimated IC50 value of 54.06 μM. The highest cell viability reduction (60%) was recorded in cells, which were exposed to 100 μM concentration. Further assays demonstrated that in the dual acridine orange/ethidium bromide staining method the cell population in the late apoptosis phase was increased in a concentration-dependent manner, which was confirmed with remarkable DNA fragmentation. Conclusion and implications: We found that the PDG-induced apoptosis in K562 cells is mediated through the caspase-3 activation both in mRNA and protein levels. Our results suggest that PDG could be a potent compound for further pharmacokinetic and pharmacodynamics studies in the in vivo model of CML.

Health organizations worldwide have warned that we are on the cusp of a “post-antibiotic era,” necessitating new approaches to combat antibiotic resistant infections. One such approach is the development of antibiotic adjuvants, which have little or no inherent antibiotic activity at their active concentrations but instead potentiate the activity of antibiotics against antibiotic-resistant bacteria. Recently, we demonstrated that meridianin D, a natural product originally reported to have activity against Staphylococcus aureus and Mycobacterium tuberculosis, possesses the ability to reverse colistin resistance in colistin resistant bacteria. As most natural product screens typically involve screening for only certain activities (anticancer, antiviral, and antimicrobial are typical), we posited that the meridianin D discovery was not unique and there are potentially many natural products that have adjuvant activity. To explore this, the National Cancer Institute (NCI) Natural Product Library Set IV was screened for adjuvant activity using four classes of antibiotics (β-lactams, aminoglycosides, macrolides, and polymyxins) against three bacterial pathogens (methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumannii, and Klebsiella pneumoniae). Sixteen compounds suppressed β-lactam resistance in MRSA, five of which effected a 16-fold reduction in the oxacillin minimum inhibitory concentration (MIC). Two natural products effectively suppressed aminoglycoside resistance in both of the Gram-negative species tested, and no hits were observed with macrolides. In contrast, a larger number of natural product adjuvants were identified when screening against colistin-resistant strains of A. baumannii and K. pneumoniae. Nine compounds reduced the colistin MIC to its breakpoint or lower (up to a 1024-fold reduction). Clorobiocin, novobiocin, and prodigiosin were most effective, reducing the colistin MIC in K. pneumoniae strain B9 to 2 μg/mL at concentrations as low as 0.625, 2.5, and 1.25 μm, respectively. Restored sensitivity to colistin with these compounds does not appear to coincide with known mechanisms of colistin resistance.

Production of green pigments has drawn great attention recently in various applications like foods, cosmetics, nutraceuticals, and pharmaceuticals as it counters the harmful effects of synthetic dyes. Use of green natural products, especially microbe-derived colours in food and cosmetics is rapidly developing for its eco-friendly nature and cost effectiveness. In this study, a red pigment producing rod-shaped, Gram-negative bacterium Serratia rubidaea HB01 was isolated from domestic sewage. The isolate exhibited wide resistance to various groups of antibiotics, including Aminoglycosides, Lincosamides, Macrolides, Nitroimidazoles, Penicillins, Quinolones, and Tetracyclines. The isolate S. rubidaea HB01 significantly produced red prodigiosin pigment (17.9 mg ml−1). The production of prodigiosin was highly pH sensitive and growth media specific. The UV–Vis spectrum of the red pigment dissolved in methanol showed a maximum absorption at 536 nm in neutral pH. Red fraction with Rf value 0.38 purified by thin layer chromatography (TLC) was further subjected to liquid chromatography and mass spectrometric (LC–MS) analysis. Moreover, a strong band of pyrrolenine (C = N) at vmax 1639 was found comparable to prodigiosin as observed from Fourier-transform infrared (FTIR) spectra. Alongside, the presence of a typical methoxy group with chemical shifts at δ 4.0 ppm and δ 58.5 ppm was revealed by 1H and 13C nuclear magnetic resonance (NMR) spectra respectively, confirming the red pigment produced to be prodigiosin. The molecular weight of the prodigiosin was identified as 323 (m/z 324, [M + H]+). Serratia species that typically develop antibiotic resistance mechanisms are already known to produce antibiotics (carbapenem and bacteriocins) and prodigiosin pigment by integrating Quorum Sensing (QS) with overlapping pigment production regulatory systems (pigP). Consequently, mutations in this regulatory region may influence the production of prodigiosin and antibiotic resistance mechanisms.

Chemotherapy failure is a major cause of recurrence and poor prognosis in colorectal cancer (CRC) patients. Inhibition of autophagy is a promising strategy to augment the cytotoxicity of chemotherapeutic agents. We identified prodigiosin, a secondary metabolite produced by various bacteria, as a novel autophagy inhibitor that interfered with the autophagic flux in CRC cells by blocking autophagosome-lysosome fusion and lysosomal cathepsin maturation, resulting in the accumulation of LC3B-II and SQSTM. Suppression of autophagy by prodigiosin sensitized the CRC cells to 5-fluorouracil (5-Fu) in vitro, and the combination treatment markedly reduced cancer cell viability partly via caspase-dependent apoptosis. Furthermore, prodigiosin and 5-Fu synergistically inhibited CRC xenograft growth in vivo without any adverse effects. In conclusion, prodigiosin inhibits late stage autophagy and sensitizes tumor cells to 5-Fu, indicating its therapeutic potential in CRC.

Monoclonal antibodies (mAbs) are active pharmaceutical ingredients in antibody drugs, produced mainly using recombinant Chinese hamster ovary (CHO) cells. The regulation of recombinant CHO cell proliferation can improve the productivity of heterologous proteins. Chemical compound approaches for cell cycle regulation have the advantages of simplicity and ease of use in industrial processes. However, CHO cells have genetic and phenotypic diversity, and the effects of such compounds might depend on cell line and culture conditions. Increasing the variety of cell cycle inhibitors is a promising strategy to overcome the dependency. Marine microorganisms are a vast and largely undeveloped source of secondary metabolites with physiological activity. In this study, we focused on secondary metabolites of marine microorganisms and evaluated their effectiveness as cell cycle inhibitory compounds. Of 720 extracts from microorganisms (400 actinomycetes and 320 filamentous fungi) collected from the Okinawan Sea, we identified nine extracts that decreased the specific growth rate and increased the specific production rate without reducing cell viability. After fractionating the extracts, the components of active fractions were estimated using time-of-flight mass spectrometry analysis. Then, four compounds, including staurosporine and undecylprodigiosin were deduced to be active compounds. These compounds have been reported to exert a cell cycle inhibitory effect on mammalian cells. These compounds might serve as additives to improve mAb production in CHO cells. This study indicates that secondary metabolites of marine microorganisms are a useful source for new cell cycle inhibitory compounds that can increase mAb production in CHO cells.

Background. Prodigiosin is a red pigment produced as a secondary metabolite by Serratia marcescens , characterized with unique tripyrrole structure and exhibits such pharmacological characteristics as antitumor, antimicrobial, antioxidant, immunodepressant, and also used in various branches of biotechnology as a natural dye or marker of petroleum products. However, pigmentation is only present in a small percentage of isolated cultures among different S. marcescens strain, therefore, the effectiveness of biotechnological productivity is primarily determined by the producer strain, as well as the rational conditions for biosynthesis. Pigment production levels are strongly influenced by various factors, such as the set and ratio of the components of the culture medium (concentration of a particular substrate, C:N ratio) and cultivation conditions (temperature, pH). Besides, the use of relatively low-cost substrates is an important condition for reducing financial costs for the production of culture media and increasing the level of biosynthesis of the target product. Therefore, the determination of the influence of the culture medium for the strains of S. marcescens and the identification of the main factors contributing to the accumulation of the pigment prodigiosin to develop biotechnologies for the production of drugs for therapeutic purposes is relevant. Objective. The purpose of the paper is investigation of pigment-forming strain of S. marcescens under cultivation conditions on the surface of solid nutrient media, determination of biochemical features, and rational cultivation conditions that contribute to the accumulation of the pigment prodigiosin. Methods. The strain of S. marcescens isolated from the bentonite clays of Kurtsivskyi deposit (Crimea, Ukraine) was cultured in Petri dishes on solid nutrient media with different temperatures, pH, carbon and nitrogen sources. The influence of various values of the studied factors was established by the level of pigment accumulation, which was determined by the gravimetric method. The acidity of the nutrient medium was determined by the potentiometric method. Results. The influence of the initial pH values of solid nutrient medium, temperature, and various sources of carbon and nitrogen on the accumulation of pigment during the cultivation of the strain S. marcescens was studied. The temperature, pH, and compounds, sources of carbon and nitrogen, favorable for obtaining the pigment, were determined. Conclusions. It was found that the rational parameters for cultivation are the temperature +27–28 °C and the acidity of the nutrient medium of 6–7, and the best sources of carbon and nitrogen for prodigiosin accumulation are glycerin and peptone (as well as casein hydrolysate, yeast extract or ammonium (nitrate) inorganic compounds), respectively.

Red pigmented marine bacteria, Pseudoalteromonas rubra strains PS1 and SB14, were isolated from two sampling locations in different ecosystems on Alor Island, Indonesia, and cultured in the laboratory. We analyzed the 16S rRNA gene sequences and examined the pigment composition and found that both strains produced cycloprodigiosin (3), prodigiosin (4), and 2-methyl-3-hexyl-prodiginine (5) as major compounds. In addition, we detected three minor compounds: prodigiosin derivatives 2-methyl-3-propyl prodiginine (1), 2-methyl-3-butyl prodiginine (2), and 2-methyl-3-heptyl-prodiginine (6). To our knowledge, this is the first report that P. rubra synthesizes not only prodigiosin and cycloprodigiosin but also four prodigiosin derivatives that differ in the length of the alkyl chain. The antimicrobial activity of cycloprodigiosin, prodigiosin, and 2-methyl-3-hexyl-prodiginine was examined by a disk-diffusion test against Escherichia coli, Staphylococcus aureus, Salmonella typhi, and Candida albicans. We found that, at a concentration of 20 μg/mL, cycloprodigiosin showed the greatest inhibition (25.1 ± 0.55 mm) against S. aureus.

Prodigiosin is a secondary metabolite, with red pigmentation, produced by Serratia marcescens. Red pigment is a natural alkaloid whose chemical structure has three pyrrole rings. Prodigiosin has been described for several biological activities, including antitumor, inducing apotosis in T and B lymphocytes. This work aimed to evaluate the cytotoxic activity of prodigiosin in NCHI-292, HEp-2, MCF-7 and HL-60 tumor cell lines. The red pigment was isolated from Serratia marcescens UFPEDA 398 biomass whose fractions were previously separated by column chromatography, purified, identified and further characterized by GC–MS and compared with the computerized library of m/z values. The pigment corresponded to prodigiosin with maximum absorption at 534 nm, molecular weight 323 and structural formula C20H25N3O. During the prodigiosin purification process a purple absorbance fraction at 272.65 nm was also observed. Significant cytotoxic effects of prodigiosin were evidenced for NCHI-292, Hep-2, MCF-7 and HL-60 tumor cell lines. The isolated purple fraction had no cytotoxic effect (IC50 11.3 µg/mL) when compared to prodigiosin (IC50 3.4 µg/mL) for the tumor cell lines studied. The MCF-7 strain was slightly more pigment resistant (IC50 5.1 µg/mL). Therefore, further studies will be needed to elucidate the antitumor mechanisms of prodigiosin action against tumor strains from flow cytometry tests. However, although these data are preliminary, it was evidenced that prodigiosin showed cytotoxic activity in tumor cell lines suggesting promising antitumor properties. In this sense, future studies on the cytotoxic and genotoxic effects of prodigiosin produced by S. marcecsens UFPEDA 398 are suggested.

The cell wall is not a target of currently used therapeutics as Mycobacterium are considered naturally resistant to most β-lactam antibiotics. Therefore, combinations of conventional antibiotics with antibiotic activity-enhancing compounds offer a productive treatment strategy and address the widespread emergence of antibiotic-resistant strains. The first area of research was the study of a comparative analysis of disk diffusion testing and the broth dilution method for evaluating the susceptibility of M. smegmatis to antimicrobial agents. A comparative analysis of the susceptibility to antimicrobial agents alone showed that M. smegmatis was the most susceptible to ceftriaxone and kanamycin, and moderately sensitive to vancomycin and prodigiosin. Compared to the susceptibility of the antibacterial combinations, the isolate was not susceptible to antibacterial combinations with prodigiosin in disk diffusion testing. The second area of research was the study of the synergic activity of prodigiosin of S. marcescens and inhibitors of cell wall synthesis manifested by their simultaneous effect on M. smegmatis. The greatest increase in the sensitivity of test-culture of mycobacteria occurred with ampicillin, benzylpenicillin, cephazolin and ceftriaxone in combination with prodigiosin of S. marcescens. The presented combination of antibiotics and prodigiosin reduce the required concentration of the antibiotic and by amplifying the effect of compounds inhibiting cell wall synthesis, thereby giving lower FICI values. These data indicate the possibility of using prodigiosin as a promising candidate for the development of "accompaniment-preparations" for antibiotics for the additional therapy of infectious diseases caused by Mycobacterium spp. and can suspend the likelihood of developing resistance to antibiotics. The cell wall is not a target of currently used therapeutics as Mycobacterium are considered naturally resistant to most β-lactam antibiotics. Therefore, combinations of conventional antibiotics with antibiotic activity-enhancing compounds offer a productive treatment strategy and address the widespread emergence of antibiotic-resistant strains. The first area of research was the study of a comparative analysis of disk diffusion testing and the broth dilution method for evaluating the susceptibility of M. smegmatis to antimicrobial agents. A comparative analysis of the susceptibility to antimicrobial agents alone showed that M. smegmatis was the most susceptible to ceftriaxone and kanamycin, and moderately sensitive to vancomycin and prodigiosin. Compared to the susceptibility of the antibacterial combinations, the isolate was not susceptible to antibacterial combinations with prodigiosin in disk diffusion testing. The second area of research was the study of the synergic activity of prodigiosin of S. marcescens and inhibitors of cell wall synthesis manifested by their simultaneous effect on M. smegmatis. The greatest increase in the sensitivity of test-culture of mycobacteria occurred with ampicillin, benzylpenicillin, cephazolin and ceftriaxone in combination with prodigiosin of S. marcescens. The presented combination of antibiotics and prodigiosin reduce the required concentration of the antibiotic and by amplifying the effect of compounds inhibiting cell wall synthesis, thereby giving lower FICI values. These data indicate the possibility of using prodigiosin as a promising candidate for the development of "accompaniment-preparations" for antibiotics for the additional therapy of infectious diseases caused by Mycobacterium spp. and can suspend the likelihood of developing resistance to antibiotics.

The work was aimed to study the synergy of the antimicrobial activity of the prodigiosin pigment with antibiotics against bacteria of the genera Bacillus, Staphylococcus and Streptococcus. The serial dilution method was used to evaluate antimicrobial compositions, which included inhibitors of cell wall synthesis: ampicillin, benzylpenicillin, vancomycin, cefazolin, and metronidazole (nitroimidazole derivatives) in combination with the pigment prodigiosin isolated from Serratia marcescens. Each combination was tested against the studied strains. The fractional inhibitory concentration index (FICI) for each combination was calculated to determine synergy, and the results were interpreted as follows: FICI ≤0.5 ‒ synergism; FICI > 4.0 ‒ antagonism; and FICI > 0.5-4 ‒ neutralism. It was shown that the ethanol extract of prodigiosin in combination with benzylpenicillin, vancomycin, cefazolin, and metronidazole interacted differently synergistically depending on the type of microorganism. The combinations of prodigiosin and metronidazole showed a synergistic effect against Bacillus subtilis, vancomycin and cefazolin against Staphylococcus aureus and benzylpenicillin against Streptococcus pyogenes. Other combinations of prodigiosin and antibiotics showed a neutral effect, and in the case of cefazolin against Str. pyogenes, even an antagonistic effect. Thus, the study showed the synergism of prodigiosin with antibiotics depending on the type of microorganism, contributed to a several-fold decrease in the minimum inhibitory and bactericidal concentrations of each component separately, and the results indicated that prodigiosin acted separately more efficiently against gram-positive non-spore-forming bacteria. This synergistic combination of antimicrobial agents had great potency to prevent bacterial resistance.

Serratia marcescens is an opportunistic pathogen that causes diverse nosocomial infections. S. marcescens has developed considerable resistance to different antibiotics and is equipped with an armory of virulence factors. These virulence factors are regulated in S. marcescens by an intercellular communication system termed quorum sensing (QS). Targeting bacterial virulence and QS is an interesting approach to mitigating bacterial pathogenesis and overcoming the development of resistance to antimicrobials. In this study, we aimed to evaluate the anti-virulence activities of secnidazole on a clinical isolate of S. marcescens. The effects of secnidazole at sub-inhibitory concentrations (sub-MICs) on virulence factors, swarming motility, biofilm formation, proteases, hemolysin activity, and prodigiosin production were evaluated in vitro. Secnidazole’s protective activity against S. marcescens pathogenesis was assessed in vivo in mice. Furthermore, a molecular docking study was conducted to evaluate the binding ability of secnidazole to the S. marcescens SmaR QS receptor. Our findings showed that secnidazole at sub-MICs significantly reduced S. marcescens virulence factor production in vitro and diminished its pathogenesis in mice. The insilico docking study revealed a great ability of secnidazole to competitively hinder the binding of the autoinducer to the SmaR QS receptor. In conclusion, secnidazole is a promising anti-virulence agent that may be used to control infections caused by S. marcescens.

Metastasis is the primary cause of death in cancer patients. Many current chemotherapeutic agents only show cytotoxic, but not antimetastatic properties. This leads to a reduction in tumor size, but allows cancer cells to disseminate, which ultimately causes patient death. Therefore, novel anticancer compounds with both effects need to be developed. In this work, we analyze the antimetastatic properties of prodigiosin and obatoclax (GX15-070), anticancer drugs of the Prodiginines (PGs) family. We studied PGs’ effects on cellular adhesion and morphology in the human primary and metastatic melanoma cell lines, SK-MEL-28 and SK-MEL-5, and in the murine melanoma cell line, B16F10A. Cell adhesion sharply decreased in the treated cells, and this was accompanied by a reduction in filopodia protrusions and a significant decrease in the number of focal-adhesion structures. Moreover, cell migration was assessed through the wound-healing assay and cell motility was severely inhibited after 24 h of treatment. To elucidate the molecular mechanisms involved, changes in metastasis-related genes were analyzed through a gene-expression array. Key genes related to cellular invasion, migration and chemoresistance were significantly down-regulated. Finally, an in vivo model of melanoma-induced lung metastasis was established and significant differences in lung tumors were observed in the obatoclax-treated mice. Altogether, these results describe, in depth, PGs’ cellular antimetastatic effects and identify in vivo antimetastatic properties of Obatoclax., This research has been funded by Instituto de Salud Carlos III (Grants PI18/00441; FIS PI10/00338) (Co-funded by European Regional Development Fund. ERDF, a way to build Europe).

The purpose of this study was to reuse cassava wastewater (CW) for scaled-up production, via the fermentation of prodigiosin (PG), and to conduct an evaluation of its bioactivities. PG was produced at the yield of high 6150 mg/L in a 14 L-bioreactor system, when the designed novel medium (7 L), containing CW and supplemented with 0.25% casein, 0.05% MgSO4, and 0.1% K2HPO4, was fermented with Serratia marcescens TNU01 at 28 °C in 8 h. The PG produced and purified in this study was assayed for some medical effects and showed moderate antioxidant, high anti-NO (anti-nitric oxide), and potential α-glucosidase inhibitory activities. Notably, PG was first reported as a novel effective α-glucosidase inhibitor with a low IC50 value of 0.0183 µg/mL. The commercial anti-diabetic drug acarbose was tested for comparison and had a lesser effect with a high IC50 value of 328.4 µg/mL, respectively. In a docking study, the cation form of PG (cation-PG) was found to bind to the enzyme α-glucosidase by interacting with two prominent amino acids, ASP568 and PHE601, at the binding site on the target enzyme, creating six linkages and showing a better binding energy score (−14.6 kcal/mol) than acarbose (−10.5 kcal/mol). The results of this work suggest that cassava wastewater can serve as a low-cost raw material for the effective production of PG, a potential antidiabetic drug candidate.

Background: Wide range of microorganisms produced secondary metabolites as microbial activities in extended habitats. Aims: The aim of this research is the extraction of the red colored pigment, prodigiosin from Serratia marcesens isolated from the soil and evaluate its antibacterial activity against different strains of oxacillin/methicillin-resistant Staphylococcus S. aureus. Study Design: Two isolates, namely, RMN1 and RMN2, belonging to the Genus, Serratia from two soil samples collected from two strategic locations in University of Abuja, Nigeria were isolated. The isolates were morphologically distinct on the basis of spore colour, aerial and substrate mycelium formation and production of diffusible pigment. Isolates were Gram stained, observed under a microscope and were seen to be Gram negative. Biochemical tests revealed that the two isolates were catalase and citrate positive, and were oxidase negative. One of the two isolates was observed to have significant antibiotic producing potential, and the antibacterial activity of the produced antibiotics (red pigment extracted from cultural supernatants of the isolates grown on Peptone glycerol agar) was assessed using the agar-well diffusion method and streaking agar method. Results: The results indicated that the pigment extracted in vitro had varying antibacterial activity at different concentrations of 500 mg/ml, 250 mg/ml, 125 mg/ml and 62.5 mg/ml against four strains of the test organism (Staphylococcus aureus) titled S1 to S4, the extracted pigment was more effective at concentration 500 mg/ml against the antibiotic resistant S. aureus with the MIC at 125 mg/ml. Conclusion: The results indicated that the soil of this region could be a good source of prodigiosin having antibacterial activity and thus enable the use of micro-organisms as biological control agents.

Cl--ion transporters (2a-2h) were synthesized based on the binding motifs of prodigiosin. Transporter 2e clearly displays Cl--ion transportation activity across both model and live cell membranes. Furthermore, 2e can disrupt Ca2+ homeostasis and increase the intracellular concentration of Ca2+ in the DLD-1 cell. This disruption can lead to Caspase-dependent apoptosis supported by CHOP expression (a marker of ER stress) and the appearance of the cleaved forms of Caspase 3 and PARP.

This is the first report of a fully annotated genomic sequence of Streptomyces spectabilis NRRL-2792, isolated and identified by The Upjohn Company in 1961. The genome was assembled into a single scaffold for annotation and analysis. The chromosome is linear, 9.5 Mb in size which is one of the largest Streptomyces genomes yet described, has a G+C content of 72%, and encodes for approximately 7943 genes. Antibiotic Secondary Metabolite Analysis Shell (antiSMASH) and Basic Local Alignment Search Tool (BLAST) bioinformatics analyses identified six complete secondary metabolite biosynthetic gene clusters for ectoine, melanin, albaflavenone, spectinomycin, 2-methylisoborneol and coelichelin. Additionally, biosynthetic clusters were identified that shared ≥ 90% gene content with complestatin, hopene, neoaureothin, or undecylprodigiosin. Thirty-one other likely secondary metabolite gene clusters were identified by antiSMASH. BLAST identified two subsets of undecylprodigiosin biosynthetic genes at polar opposites of the chromosome; their duplication was subsequently confirmed by primer walking.

The potential of flow cytometry for the study of changes in prodigiosin on the cell surface of Serratia marcescens is of academic and practical interest. This is because S. marcescens can produce prodigiosin, a secondary metabolite, with potential use as a cancer-cell inhibitor. In this study, three groups of bacterial cultures with different carbon sources were compared, and the effect of the addition of cAMP to the sucrose-based culture was studied. Both cellular morphology and DNA content were detected by flow cytometry, rendering a broad description of the bacterial behavior. It is the first use of flow cytometry to investigate the dynamics of prodigiosin on the surface of S. marcescens during growth in different media. The fluorescence intensity is related to the DNA content, the forward-scattered light is related to cell volume, and the side-scattered light is related to the surface morphology, especially the surface prodigiosin. These may contribute to the potential development of a bacterial metabolic monitoring strategy using both DNA content analysis and bacterial morphology based on flow cytometry technique.

Serratia marcescens is a bacterial species widely found in the environment, which very efficiently colonizes mosquitoes. In this study, we isolated a red-pigmented S. marcescens strain from our mosquito colony (called S. marcescens VA). This red pigmentation is caused by the production of prodigiosin, a molecule with antibacterial properties. To investigate the role of prodigiosin on mosquito-S. marcescens interactions, we produced two white mutants of S. marcescens VA by random mutagenesis. Whole genome sequencing and chemical analyses suggest that one mutant has a nonsense mutation in the gene encoding prodigiosin synthase, while the other one is deficient in the production of several types of secondary metabolites including prodigiosin and serratamolide. We used our mutants to investigate how S. marcescens secondary metabolites affect the mosquito and its microbiota. Our in vitro tests indicated that S. marcescens VA inhibits the growth of several mosquito microbiota isolates using a combination of prodigiosin and other secondary metabolites, corroborating published data. This strain requires secondary metabolites other than prodigiosin for its proteolytic and hemolytic activities. In the mosquito, we observed that S. marcescens VA is highly virulent to larvae in a prodigiosin-dependent manner, while its virulence on adults is lower and largely depends on other metabolites.

Prodiginines are bacterial red polypyrrole pigments and multifaceted secondary metabolites. These agents have anti-proliferative, immunosuppressive, antimicrobial, and anticancer effects. Recent analysis revealed that prodigiosin hypersensitizes Serratia marcescens to gamma radiation. In the present study, we report the cytotoxicity and genotoxicity properties of undecylprodigiosin and butylcycloheptylprodigiosin in the presence and absence of radiation through the MTT and alkaline comet experiments.Findings demonstrated that undecylprodigiosin was at least a fivefold more cytotoxic at low radiation doses (1 and 3 Gy) on both MCF7 and HDF lines rather than in the absence or high radiation doses (5 Gy) (P value 0.05). Although butylcycloheptylprodigiosin toxicity on MCF7 and HDF was dose-dependent, it was not influenced by any radiation doses (P value 0.05). Comet findings confirmed that these compounds' genotoxicity is only dose-dependent. Radiation had no significant effects on DNA damage on any of the cells (P value 0.05).In general, it can be concluded that the prodiginines are cytotoxic agents that act as a double-edged sword, radiosensitizers and radio-protective, respectively at low and high radiation doses in cancer treatment process. As the results they could be used in antitumor therapies very soon.

As an investigative study, the potent bacterium Serratia marcescens SB08 was screened from the enteric gut of sulfur butterfly (Kricogonia lyside). Its pigment potential was tested, and the pigment was identified as prodigiosin by structural studies using High Performance Liquid Chromatography (HPLC), Gas Chromatography–Mass Spectroscopy (GC–MS), Fourier Transform Infrared Spectroscopy (FTIR) and Nuclear Magnetic Resonance (NMR). Various conditions, including pH, reaction time, temperature, color intensity, and fastness properties, were studied for pure silk, China silk, and cotton yarns, and the conditions for effective dyeing were optimized. Further, the pigment’s antimicrobial pursuit was tested to counter the common pathogens Bacillus subtilis MTCC2388, Escherichia coli MTCC443, Klebsiella pneumonia MTCC109, Proteus vulgaris MTCC1771, and Pseudomonas aeruginosa MTCC1688. The pigment was largely effectual and exhibited utmost zones of inhibition, thus demonstrating the finest antimicrobial effect against the microbes tested. The textile yarn materials soaked with this intrinsic dye pigment also exhibited antimicrobial action.

Prodigiosin is a red pigment produced by Serratia marcescens with anticancer, antimalarial, and antibacterial effects. In this study, we extracted and identified a red pigment from a culture of S. marcescens strain ZPG19 and investigated its effect on the growth performance and intestinal microbiota of Kunming mice. High-performance liquid chromatography/mass spectrometry revealed that the pigment had a mass-to-charge ratio (m/z) of 324.2160, and thus it was identified as prodigiosin. To investigate the effect of prodigiosin on the intestinal microbiota, mice (n = 5) were administered 150 μg/kg/d prodigiosin (crude extract, 95% purity) via the drinking water for 18 days. Administration of prodigiosin did not cause toxicity in mice. High-throughput sequencing analysis revealed that prodigiosin altered the cecum microbiota abundance and diversity, the relative abundance of Desulfovibrio significantly decreased, whereas Lactobacillus reuteri significantly increased. This finding indicates that oral administration of prodigiosin has a beneficial effect on the intestinal microbiota of mice. As prodigiosin is non-toxic to mouse internal organs and improves the mouse intestinal microbiota, we suggest that it is a promising candidate drug to treat intestinal inflammation.

Lactobacillus acidophilus ghosts (LAGs) with the unique safety of a probiotic, inherent tropism for colon cells and multiple bioactivities offer great promise as drug carrier for colon targeting. We report herein on a novel bioinspired drug delivery system against colorectal cancer (CRC) cells based on LAGs functionalized with prodigiosin (PG), a proapoptotic bacterial metabolite. LAGs were prepared by a chemical method and highly purified by density gradient centrifugation. Multiple microscopic and staining techniques characterized LAGs by a relatively small size, size uniformity, a relatively large internal volume devoid of cytoplasmic and genetic materials and an intact negatively charged envelop. PG was highly bound to LAGs cell wall, generating a physiologically stable bioactive entity (PG-LAGs) active against HCT116 CRC cells at the cellular and molecular levels. Cell viability data underlined cytotoxicity of PG and LAGs and LAGs-induced enhancement of PG selectivity for HCT116 cells. Combination and Dose reduction indices anticipating dose reduction of PG and LAGs. Molecularly, PG-LAGs significantly modulated the expression of apoptosis-related biomarkers, caspase 3, P53 and BCL2, in favor of cytotoxicity against HCT116 cells relative to PG and 5-fluorouracil. Accordingly, LAGs offer promise as novel drug carrier for targeted colon delivery and PG-LAGs may bring therapeutic benefits in colorectal carcinoma.

Funder: Frances and Augustus Newman Foundation, Funder: Emmanuel College, University of Cambridge, Funder: Cambridge Commonwealth Trust, A biosynthetic pathway for the red-antibiotic, prodigiosin, was proposed over a decade ago but not all the suggested intermediates could be detected experimentally. Here we show that a thioester that was not originally included in the pathway is an intermediate. In addition, the enzyme PigE was originally described as a transaminase but we present evidence that it also catalyses the reduction of the thioester intermediate to its aldehyde substrate.

Prodigiosin, a red linear tripyrrole pigment, has long been recognised for its antimicrobial property. However, the physiological contribution of prodigiosin to the survival of its producing hosts still remains undefined. Hence, the aim of this study was to investigate the biological role of prodigiosin from Serratia marcescens, particularly in microbial competition through its antimicrobial activity, towards the growth and secreted virulence factors of four clinical pathogenic bacteria (methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecalis, Salmonella enterica serovar Typhimurium and Pseudomonas aeruginosa) as well as Staphylococcus aureus and Escherichia coli. Prodigiosin was first extracted from S. marcescens and its purity confirmed by absorption spectrum, high performance liquid chromatography (HPLC) and liquid chromatography-tandem mass spectrophotometry (LC-MS/MS). The extracted prodigiosin was antagonistic towards all the tested bacteria. A disc-diffusion assay showed that prodigiosin is more selective towards Gram-positive bacteria and inhibited the growth of MRSA, S. aureus and E. faecalis and Gram-negative E. coli. A minimum inhibitory concentration of 10 μg/μL of prodigiosin was required to inhibit the growth of S. aureus, E. coli and E. faecalis whereas > 10 μg/μL was required to inhibit MRSA growth. We further assessed the effect of prodigiosin towards bacterial virulence factors such as haemolysin and production of protease as well as on biofilm formation. Prodigiosin did not inhibit haemolysis activity of clinically associated bacteria but was able to reduce protease activity for MRSA, E. coli and E. faecalis as well as decrease E. faecalis, Salmonella Typhimurium and E. coli biofilm formation. Results of this study show that in addition to its role in inhibiting bacterial growth, prodigiosin also inhibits the bacterial virulence factor protease production and biofilm formation, two strategies employed by bacteria in response to microbial competition. As clinical pathogens were more resistant to prodigiosin, we propose that prodigiosin is physiologically important for S. marcescens to compete against other bacteria in its natural soil and surface water environments.

Pseudomonas putida is a metabolically versatile bacterium grown in various habitats that have been intensively studied with regard to its potential to produce various products of industrial relevance. Due to its special features like robust metabolism, a broad tolerance to toxic compounds and oxidative stress, and easiness of genetic modification, this bacterium is becoming microbial efficient cell factories for many natural products with diverse biological functions. This chapter provides an overview of P. putida as a host microorganism for the recombinant synthesis of applicable bioproducts such as polyhydroxyalkanoates, surfactants, terpenoids, and prodigiosin. This overview of bioproducts that could be produced by heterologous gene expression and strain engineering confirms P. putida potential to be a workhorse for industrial applications being a good provider of the molecular machinery.

Nowadays, pigments from microbial sources have gained much importance due to its substantial medical and industrial welfares. In this regard, the present book chapter discusses some impactful methodologies regarding the improved production of prodigiosin drug—a promising supplement of synthetic colour. Prodigiosin is a vivid red colour pigment mainly synthesized by bacteria Serratia marcescens. Other than its significant contribution towards the cosmetic and food industry, it also poses antifungal, antibacterial, immunosuppressive and antiproliferative activities. Optimization of media components, scale-up study and biokinetic analysis from wild type and recombinant sources have been thoroughly discussed in this chapter. Particular emphasis was put forward on its nanotechnological synthesis and drug delivery for various diseases. Efficient extraction practice, estimation by different analytical instruments and purification of the final product were also highlighted in a best possible way.

Introduction. Nosocomial contaminants such as Pseudomonas aeruginosa and Serratia marcescens are increasingly developing resistance to many antibiotics. One of the promising alternatives that may complement, if not substitute, the use of antibiotics is quorum quenching, the process of interfering with chemical signals that mediate communication between microorganisms. Eleusine indica, a ubiquitous grass used traditionally to treat infections, has been shown to contain metabolites, such as fatty acid derivatives and p-coumaric acid, capable of quorum quenching. To date, there has been no study on the quorum quenching activity of E. indica. Objectives. This study aimed to determine the in vitro activity of crude ethanolic extract of E. indica leaves against selected quorum-sensing regulated virulence factors of P. aeruginosa and S. marcescens. Methodology. E. indica leaves were collected, washed, air-dried, and homogenized. Following ethanolic extraction and rotary evaporation, the extract was screened for antimicrobial activity through disk diffusion test and broth microdilution assay. The quorum quenching activity of the extract against P. aeruginosa was measured through swarming motility assay, while the activity against S. marcescens was measured through swarming motility and pigment inhibition assays. The quorum quenching assays were conducted in triplicates, and analysis of variance (ANOVA) was performed to identify differences among the treatment groups. Results. Disk diffusion test revealed that no zones of inhibition formed against both P. aeruginosa and S. marcescens for varying concentrations of up to 200 mg/mL of the crude extract. Likewise, the MIC of the extract against both P. aeruginosa and S. marcescens was determined to be >200 mg/mL. However, it was shown that the extract, at 50 mg/mL, has statistically significant activity (p

Cisplatin-based treatment is the standard of care therapy for urothelial carcinomas. However, complex cisplatin resistance mechanisms limit the success of this approach. Both apoptosis and autophagy have been shown to contribute to this resistance. Prodigiosin, a secondary metabolite from various bacteria, exerts different biological activities including the modulation of these two cellular stress response pathways. We analyzed the effect of prodigiosin on protein levels of different autophagy- and apoptosis-related proteins in cisplatin-sensitive and -resistant urothelial carcinoma cells (UCCs). Furthermore, we investigated the effect on cell viability of prodigiosin alone or in combination with cisplatin. We made use of four different pairs of cisplatin-sensitive and -resistant UCCs. We found that prodigiosin blocked autophagy in UCCs and re-sensitized cisplatin-resistant cells to apoptotic cell death. Furthermore, we found that prodigiosin is a potent anticancer agent with nanomolar IC50 values in all tested UCCs. In combination studies, we observed that prodigiosin sensitized both cisplatin-sensitive and -resistant urothelial carcinoma cell lines to cisplatin treatment with synergistic effects in most tested cell lines. These effects of prodigiosin are at least partially mediated by altering lysosomal function, since we detected reduced activities of cathepsin B and L. We propose that prodigiosin is a promising candidate for the therapy of cisplatin-resistant urothelial carcinomas, either as a single agent or in combinatory therapeutic approaches.

Acinetobacter baumannii is gram negative opportunistic coccobacilli,the most important agent in nosocomial infections with high mortality rate. This bacteria is characterized by (biochemical tests, polymerase chain reaction (PCR) and vitek-2 system). The antibiotic susceptibility result of A. baumannii isolates were shown resistant to (Methicillin, Nitrofurantion), while sensitive to (colistin, Ciprofloxacin).This study was aimed to biosynthesis of titanium dioxide nanoparticles by using prodigiosin pigment produced from clinical isolate Serratia marcescens as reducing and stabilizing agent for Titanium dioxide nanoparticles (TiO2 NPs) and used as antibacterial agent for Acinetobacter baumannii isolated from different clinical sources. TiO2 NPs synthesized by using titanium chloride TiCl4 (5 ml/50 ml) in deionized water with concentration of prodigiosin (10 mg/ml)and adjusted pH at 7 and the temperature at 50 ˚C. TiO2NPs synthesized was Characterized by various technique, such as (AFM , UV-VIS, FTIR , XRD and FE-SEM ). The result showed that wavelength(366)nm was optimum for TiO2NPs that have crystalline shape at average volume (47.52 nm). Green synthesized TiO2 NPs have shown several applications such as biomedical, anticancer, bio sensing, catalysis etc.

After separation of bacterial colonies on solid plates, purification, and screening through the agar cup-plate method, an antibiotic-resistant bacterial isolate was obtained, and named strain L20190601, the 16S rRNA gene sequence data of strain L20190601 to GenBank, NCBI have provided GenBank accession number MW931615. 16S rRNA gene sequencing revealed that this isolate was highly similar to a number of Streptomyces species. Among them, the homology with S. spectabilis was the highest, reaching 99.9, together with curved hyphal morphology and biochemical tests, allowed us to identify strain L20190601 as S. spectabilis. The red pigment produced by S. spectabilis strain L20190601 was structurally identified. An acid–base color reaction assay showed that when this pigment was dissolved in a solution at pH 3.0 and 9.0, the color of the solution was red and yellow, respectively. In addition, the analysis of absorption spectra revealed that at pH 8.0 and 3.0, the maximum absorption peaks were at 466 and 531 nm, respectively. These results are consistent with the spectral absorption characteristics of metacycloprodigiosin reported in the literature. Moreover, the retention time of purified pigments was identical to those of standard metacycloprodigiosin solutions. Mass spectrometry analysis revealed that the molecular weight of the red compound was 392.2 [M + H]+. Finally, metacycloprodigiosin was found to be effective against eight clinically common pathogens: Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Streptococcus pyogenes, Pseudomonas aeruginosa, Bacillus typhi, Candida albicans, and Trichophyton rubrum. In summary, metacycloprodigiosin exhibited strong antibacterial activity and a broad antibacterial spectrum, and thus is a promising compound for the development of a new type of antibacterial drug.

Prepared two concentration of four new enriched media for isolation of some pathogenic bacteriaincluding Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Serratia marcescens andidentification of Serratiamarcescens that produce red pigment (prodigiosin) . The first concentration 12.5 g/lof plant extracte showed heavy growth of pathogenic bacteria on the four media . The second concentration25 g/l showed also growth of the pathogenic bacteria incubation in 37°C for 24h except on the Elettariacardemomum agar and, Fenugreek (Trigonella foenum-graecum) seeds agar. Serratia marcescens producered pigment on all the new media in both concentration . All isolates produce protease enzyme on Linumusitatissium seed agar . The result is a synthesis enrichment and inexpensive medium for different speciesof bacteria like Linumusitatissium enriched with a different materials and salt as amineral that suitable forgrowth organism without any morphological change of metabolisms feature, also identification Serratiamarcescens by produce red pigment that important in medical with a wide range of biological activities.

The present study emphasizes the production and optimization of prodigiosin (PG) pigment from Serratia marcescens strain CSK, which was isolated from Shevaroy Hills, Salem district, Tamil Nadu, India. The response surface methodology analysis was applied for the optimization process of PG production. The maximum production of PG (2950 mg/L) was obtained at pH 7.0 with the addition of tryptophan (4.0 g/L) and sucrose (3.0 g/L) with 60 h of incubation. Further, the PG was characterized using high-performance liquid chromatography, Fourier-transform infrared spectroscopy, and gas chromatography-mass spectrometry. The purified PG exhibited strong antioxidant and antibacterial activities. Also, PG's cytotoxic effects against human breast cancer (MCF-7) cells were observed through acridine orange-ethidium bromide (AO-EB) and Hoechst staining. Molecular dockingstudies revealed that PG could bind positively to the caspase-3 (breast cancer protein 1RE1) binding site with a binding energy score of 17.37 kcal/mol. Overall, the novel PG was found to be an anticancer drug for potential applications in the pharmaceutical industry.

The emergence of multidrug-resistant (MDR) bacteria is on the rise and the situation has been worsening with each passing day, which is evident from the outpouring number of reports about how more and more pathogens are becoming resistant to even the third and fourth generations of antibiotics. Lately, combination therapies or drug synergy have been giving promising results in curbing infections since it delineates its action on multiple aspects as compared to monotherapies. In this study, we used prodigiosin, a bacterial pigment endowed with magnificent biological properties, in combination with six antibiotics to study its effect on Pseudomonas aeruginosa, Staphylococcus aureus and Chromobacterium violaceum. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of prodigiosin against the test organisms was determined and a checkerboard assay of prodigiosin with various antibiotic combinations was performed with an aim to abate antimicrobial resistance. MIC and MBC of prodigiosin was obtained in the range of 4–16 μg/mL, which was lower than that of most test antibiotics. Coupling prodigiosin with other test antibiotics exhibited an excellent synergy profile against all test organisms and the effects were reported to be either synergistic or additive. In the case of S. aureus and C. violaceum, all combinations were found to be synergic, and remarkably for S. aureus, FBC index was reported to be as low as ≤0.25 with all of the test antibiotics. Therefore, it is deduced that prodigiosin augments and intensifies the action of antibiotics, and results in a double-whammy against the MDR strains., Highlights • Prodigiosin showed excellent bactericidal activity against P. aeruginosa, S. aureus and C. violaceum. • Prodigiosin in combination with antibiotics exhibited synergic effect in majority of the cases against all test pathogens. • For S. aureus, prodigiosin-antibiotic combinations showed excellent synergic effect with an FBC index as low as ≤0.25. • Prodigiosin augments the action of antibiotics against pathogenic bacteria.

Prodigiosins (PGs) are a family of natural red pigments with anticancer activity, and one member of the family has entered clinical phase II trials. However, the anticancer mechanisms of PGs remain largely unclear. This study was designed to investigate the molecular basis of anticancer activity of UP, a derivative of PGs, in P388 cells. By introducing pharmacological inhibitors and utilizing a variety of analytical approaches including western blotting, flow cytometry and confocal laser microscopy, we found that UP inhibited proliferation of P388 via arresting cells at G2/M phase and inducing cells apoptosis, which was related to the activation of P38, JNK rather than ERK1/2 signaling. ROS regeneration and acidification in cells appear not involved in UP induced apoptosis. Furthermore, utilizing mass spectrometry, sucrose density gradient fractionation and immunofluorescence staining, we discovered that UP was apparently located at ribosome. These results together indicate that ribosome may be the potential target of UP in cancer cells, which opened a new avenue in delineating the anticancer mechanism of PGs.

Atherosclerosis is a chronic inflammatory disease, whose progression and stability are modulated, among other factors, by an innate and adaptive immune response. Prodiginines are bacterial secondary metabolites with antiproliferative and immunomodulatory activities, however, their effect on the progression or vulnerability of atheromatous plaque has not been evaluated. This study assessed the therapeutic potential of prodigiosin and undecylprodigiosin on inflammatory marker expression and atherosclerosis. An in vitro and in vivo study was carried out. Migration, low-density lipoprotein (LDL) uptake and angiogenesis assays were performed on cell types involved in the pathophysiology of atherosclerosis. In addition, male LDL receptor null (Ldlr-/-) C57BL/6J mice were treated with prodigiosin or undecylprodigiosin for 28 days. Morphometric analysis of atherosclerotic plaques, gene expression of atherogenic factors in the aortic sinus and serum cytokine quantification were performed. The treatments applied had slight effects on the in vitro tests performed, highlighting the inhibitory effect on the migration of SMCs (smooth muscle cells). On the other hand, although no significant difference in atherosclerotic plaque progression was observed, gene expression of IL-4 and chemokine (C-C motif) ligand 2 (Ccl2) was downregulated. In addition, 50 &micro, g/Kg/day of both treatments was sufficient to inhibit circulating tumor necrosis factor alpha (TNF-&alpha, ), interleukin-2 (IL-2) and interferon-gamma (IFN-&gamma, ) in serum. These results suggested that prodigiosin and undecylprodigiosin modulated inflammatory markers and could have an impact in reducing atherosclerotic plaque vulnerability.

Herpes simplex virus (HSV) is among the most prevalent viral infections worldwide and remains incurable. While nucleoside analogs are used to relieve symptoms of infection, they suffer from having serious adverse effects and are unable to abolish the virus from the host. Here, we demonstrate a unique antiviral effect of prodigiosin (PG), a natural secondary metabolite produced by Serratia marcescens, on HSV infection. We show that PG naturally exerts antiviral activity against HSV-1 and HSV-2 infections. PG treatment resulted in robust inhibition of viral replication in vitro and ex vivo in cultured porcine corneas. Additionally, PG protected against HSV-1 infection and disease progression in a murine model of ocular infection. In our quest to determine the molecular mechanisms of its antiviral activity, we show that PG specifically inhibits NF-κB and Akt signaling pathways and promotes accelerated cell death in HSV-infected cells. Our findings reveal novel antiviral properties of PG, suggesting its high potential as an alternative treatment for herpetic diseases. They also provide new information on antiviral effects of HSV-bacterial metabolite interactions. IMPORTANCE In this article, we provide a new role for a commonly found bacterial pigment in controlling herpes simplex virus infection, for which diverse and multimodal antiviral agents are needed to prevent drug resistance. Serratia marcescens is a red pigment (prodigiosin)-producing Gram-negative bacillus that is naturally found in soil and water. It is associated with many kinds of human infections, including wound and eye infections, and meningitis. Taking cues from previous studies on prodigiosin, including possible proapoptotic anticancer properties, we investigated how it might affect HSV infection. Interestingly, we found that it is a potent virucidal compound that disrupts host signaling pathways needed for HSV growth and survival. The mode of antiviral action suggests potentially broad activity against enveloped viruses. Our results also indicate that interactions with commensal bacteria may inhibit HSV infection, underscoring the importance of studying these microbial metabolites and their implications for viral pathogenesis and treatment.

Prodiginines and tambjamines are anion-selective ionophores capable of facilitating the transport of anions across the plasma membrane in mammalian cells. One of the potential applications of these anionophores is the possibility of employing them as a substitutive therapy for pathologies involving anion channels, as in cystic fibrosis. We have studied the interaction of a large anion as gluconate with three prodiginine- and two tambjamine-like compounds. Apparent dissociation constants for the chloride, iodide and gluconate complexes were estimated from iodide influx experiments in mammalian cells exposed to different extracellular anion combinations. Our experiments indicate that gluconate is not transported by the prodiginines, leaving the anionophores free to transport chloride and iodide. Conversely, gluconate would be transported to some extent by the tambjamines, competing with halides for the anionophores, and consequently reducing their flux. This might be related to the different structural features of both families of compounds. These data have important implications for the selection of impermeable anions in the analysis of the anionophore mechanism.

Cheap and efficient bioactive materials capable of producing potable water are in high demand. We synthesized bioactive prodigiosin-conjugated iron-oxide-activated carbon composite ([Ac]F@Fe3O4–PG) for the effective removal of microbial contaminants without biofilm formation. The disinfection effect of [Ac]F@Fe3O4–PG was investigated against antibiotic-resistant Escherichia coli and Bacillus cereus. The reactive oxygen species, glutathione concentration, and intracellular leakages assay, zeta potential, atomic force microscopy, scanning electron microscopy, and fluorescence microscopy were performed to understand the mechanistic route of bacterial disinfection. Results demonstrate the bacterial cell membrane damage due to the surface charge neutralization by cationic [Ac]F@Fe3O4–PG, thereby affecting the transport system of the cells. The generation of reactive oxygen species further triggered programmed bacterial cell death with apoptosis-like changes in cellular morphology. We demonstrate that the [Ac]F...