Prodigiosin Inhibits Transforming Growth Factor ß Signaling by Interfering Receptor Recycling and Subcellular Translocation in Epithelial Cells.

Prodigiosin (PG) is a naturally occurring polypyrrole red pigment produced by numerous microorganisms including some Serratia and Streptomyces strains. PG has exhibited promising anticancer activity; however, the molecular mechanisms of action of PG on malignant cells remain ambiguous. Transforming growth factor-ß (TGF-ß) is a multifunctional cytokine that governs a wide array of cellular processes in development and tissue homeostasis. Malfunctions of TGF-ß signaling are associated with numerous human cancers. Emerging evidence underscores the significance of internalized TGF-ß receptors and their intracellular trafficking in initiating signaling cascades. In this study, we identified PG as a potent inhibitor of the TGF-ß pathway. PG blocked TGF-ß signaling by targeting multiple sites of this pathway, including facilitating the sequestering of TGF-ß receptors in the cytoplasm by impeding the recycling of type II TGF-ß receptors to the cell surface. Additionally, PG prompts a reduction in the abundance of receptors on the cell surface through the disruption of the receptor glycosylation. In human Caucasian lung carcinoma cells and human hepatocellular cancer cell line cells, nanomolar concentrations of PG substantially diminish TGF-ß-triggered phosphorylation of Smad2 protein. This attenuation is further reflected in the suppression of downstream target gene expression, including those encoding fibronectin, plasminogen activator inhibitor-1, and N-cadherin. SIGNIFICANCE STATEMENT: Prodigiosin (PG) emerges from this study as a potent TGF-ß pathway inhibitor, disrupting receptor trafficking and glycosylation and reducing TGF-ß signaling and downstream gene expression. These findings not only shed light on PG's potential therapeutic role but also present a captivating avenue towards future anti-TGF-ß strategies.

The Golgi stacking protein GRASP55 is targeted by the natural compound prodigiosin.

BACKGROUND: The bacterial secondary metabolite prodigiosin has been shown to exert anticancer, antimalarial, antibacterial and immunomodulatory properties. With regard to cancer, it has been reported to affect cancer cells but not non-malignant cells, rendering prodigiosin a promising lead compound for anticancer drug discovery. However, a direct protein target has not yet been experimentally identified. METHODS: We used mass spectrometry-based thermal proteome profiling in order to identify target proteins of prodigiosin. For target validation, we employed a genetic knockout approach and electron microscopy. RESULTS: We identified the Golgi stacking protein GRASP55 as target protein of prodigiosin. We show that prodigiosin treatment severely affects Golgi morphology and functionality, and that prodigiosin-dependent cytotoxicity is partially reduced in GRASP55 knockout cells. We also found that prodigiosin treatment results in decreased cathepsin activity and overall blocks autophagic flux, whereas co-localization of the autophagosomal marker LC3 and the lysosomal marker LAMP1 is clearly promoted. Finally, we observed that autophagosomes accumulate at GRASP55-positive structures, pointing towards an involvement of an altered Golgi function in the autophagy-inhibitory effect of this natural compound. CONCLUSION: Taken together, we propose that prodigiosin affects autophagy and Golgi apparatus integrity in an interlinked mode of action involving the regulation of organelle alkalization and the Golgi stacking protein GRASP55. Video Abstract.

Multicopy expression of sigma factor RpoH reduces prodigiosin biosynthesis in Serratia marcescens FS14.

Regulation of prodigiosin biosynthesis is received wide attention due to the antimicrobial, immunosuppressive and anticancer activities of prodigiosin. Here, we constructed a transposon mutant library in S. marcescens FS14 to identify genes involved in the regulation of prodigiosin biosynthesis. 62 strains with apparently different colors were obtained. Identification of the transposon insertion sites revealed that they are classified into three groups: the coding region of cyaA and two component system eepS/R and the promoter region of rpoH. Since the effect of cyaA and eepS/R genes on prodigiosin was extensively investigated in Serratia marcescens, we chose the mutant of rpoH for further investigation. Further deletion mutation of rpoH gene showed no effect on prodigiosin production suggesting that the effect on prodigiosin production caused by transposon insertion is not due to the deletion of RpoH. We further demonstrated that multicopy expression of RpoH reduced prodigiosin biosynthesis indicating that transposon insertion caused RpoH enhanced expression. Previous results indicate that RpoS is the sigma factor for transcription of pig gene cluster in FS14, to test whether the enhanced expression of RpoH prevents prodigiosin by competing with RpoS, we found that multicopy expression of RpoS could alleviate the prodigiosin production inhibition by enhanced RpoH. We proposed that multicopy expressed RpoH competes with RpoS for core RNA polymerase (RNAP) resulting in decreased transcription of pig gene cluster and prodigiosin production reduction. We also demonstrated that RpoH is not directly involved in prodigiosin biosynthesis. Our results suggest that manipulating the transcription level of sigma factors may be applied to regulate the production of secondary metabolites.

Neuroprotective efficacy of the bacterial metabolite, prodigiosin, against aluminium chloride-induced neurochemical alternations associated with Alzheimer's disease murine model: Involvement of Nrf2/HO-1/NF-κB signaling.

Prodigiosin (PDG) is a bacterial metabolite with numerous biological and pharmaceutical properties. Exposure to aluminium is considered a root etiological factor in the pathological progress of Alzheimer's disease (AD). Here, in this investigation, we explored the neuroprotective potential of PDG against aluminium chloride (AlCl3 )-mediated AD-like neurological alterations in rats. For this purpose, rats were gavaged either AlCl3 (100 mg/kg), PDG (300 mg/kg), or both for 42 days. As a result of the analyzes performed on the hippocampal tissue, it was observed that AlCl3 induced biochemical, molecular, and histopathological changes like those related to AD. PDG pre-treatment significantly decreased acetylcholinesterase activity and restored the levels of brain-derived neurotrophic factor, monoamines (dopamine, norepinephrine, and serotonin), and transmembrane protein (Na+ /K+ -ATPase). Furthermore, PDG boosted the hippocampal antioxidant capacity, as shown by the increased superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione contents. These findings were accompanied by decreases in malondialdehyde and nitric oxide levels. The antioxidant effect may promote the upregulation of the expression of antioxidant genes (Nrf2 and HO-1). Moreover, PDG exerted notable anti-inflammatory effects via the lessening of interleukin-1 beta, tumor necrosis factor-alpha, cyclooxygenase-2, nuclear factor kappa B, and decreases in the gene expression of inducible nitric oxide synthase. In addition, noteworthy decreases in pro-apoptotic (Bax and caspase-3) levels and increases in anti-apoptotic (Bcl-2) biomarkers suggested an anti-apoptotic effect of PDG. In support, the hippocampal histological examination validated the aforementioned changes. To summarize, the promising neuromodulatory, antioxidative, anti-inflammatory, and anti-apoptotic activities of PDG establish it as a potent therapeutic option for AD.

Structures, biosynthesis, and bioactivities of prodiginine natural products.

Prodiginines are a large family of microbial secondary metabolites with a core structure of tripyrrole rings. They exhibit not only diverse chemical structures but also rich biological activities, such as anti-cancer, anti-microbial, anti-algae, anti-parasitic, pesticides, and UV radiation resistance. The preferred cytotoxicity to cancer cells rather than normal cells indicates a good biological selectivity and safety, which makes the prodiginines promising candidates for drug development and novel additives for food processing. Until now, 33 prodiginine natural products have been identified in various bacteria, including Serratia, Hahella, Pseudoalteromonas, Vibrio, Zooshikella, Streptomyces, and Actinomadura. However, most efforts are still focused on the star molecule prodigiosin, while little yet is known about other prodiginine members, which retards the research and application of prodiginine compounds. To gain insight into the prodiginine family, we reviewed the recent discoveries on their chemical structures, biosynthesis, biological activities, and mechanisms of action. We believe this article will provide a guideline for new research on prodiginines, such as the discovery of new congeners and drug development. KEY POINTS: • The prodiginines are a large family of natural products with a core structure of tripyrrole rings and exhibit various bioactivities. • The prodiginines have a widespread distribution among many environmental microbes and diverse biosynthetic pathways, indicating important ecological roles and a great potential for new congeners. • The potent biological activities and good selectivity of action make prodiginines good lead compounds for drug development.

Prodigiosin inhibits the proliferation of glioblastoma by regulating the KIAA1524/PP2A signaling pathway.

Prodigiosin (PG), a member of a family of natural red pigments produced by a variety of bacteria, was first discovered in Serratia marcescens. PG has been reported to have an apoptosis-inducing effect in many cancers, such as lymphoma, colon cancer and nasopharyngeal carcinoma. For this study, we used three glioblastoma (GBM) cell lines (LN229, U251 and A172) to explore the effect of prodigiosin on GBM cells. A CCK8 assay was used to evaluate cell viability. We determinedthe cell cycle distribution by flow cytometry and measured proliferation by an EdU incorporation assay. The expression of different molecules was investigated by western blotting and RT-PCR. We further confirmed our results by plasmid transfection and lentiviral transduction. The LN229 xenograft model was used to study the effect of prodigiosin in vivo. We confirmed that prodigiosin played an anticancer role in several GBM cell lines through the KIAA1524/PP2A/Akt signalling pathway. Prodigiosin inhibited the protein expression of KIAA1524 by suppressing its transcription, which led to activation of PP2A. Afterward, PP2A inhibited the phosphorylation of Akt, thereby inducing increased expression of p53/p21. Furthermore, it was verified that prodigiosin inhibited the KIAA1524/PP2A/Akt axis in vivo in the LN229 xenograft model. These data improve the understanding of the anticancer effects of prodigiosin and further highlight the potential of prodigiosin for the development of anti-glioma drugs.

Cd2+ tolerance and removal mechanisms of Serratia marcescens KMR-3.

Heavy metal contamination is a global issue, with cadmium (Cd2+) and its treatment becoming major environmental challenge that could be solved by microbial restoration, an eco-friendly technique. Serratia marcescens KMR-3 exhibits high tolerance and removal rate of Cd2+ (≤500 mg/L). Here, we aimed to explore mechanisms underlying tolerance to and removal of Cd2+ by KMR-3. Scanning electron microscopy, X-ray photoelectron spectroscopy, and Fourier transform infrared spectrometry were conducted to analyze characteristics of the KMR-3 biofilm and Cd2+ combined forms. The results revealed varying degrees of cell adhesion, membrane thickening, and shrinkage on the surface of the bacteria. The binding elements, electronic binding energy, and functional groups on the surface of the bacteria exhibited changes. Furthermore, the biofilm amount following treatment with Cd2+ was 1.5-3 times higher than that in the controls, treatment with Cd2+ substantially enhanced biofilm generation and increased Cd2+ adsorption. Cd2+ adsorption by its own secondary metabolite prodigiosin produced by KMR-3 was enhanced by 19.5 % compared with that observed without prodigiosin. Through transcriptome sequencing and RT-qPCR, we observed that Znu protein-chelating system regulated gene expression (znuA, znuB, and znuC), and the efflux mechanism of the P-type ATPase regulated the expression of genes (zntA, zntB, and zntR), which were significantly enhanced. Through the combined action of various strategies, KMR-3 demonstrated a high tolerance and removal ability of Cd2+, providing a theoretical basis to treat Cd2+ pollution.

Extraction of the Anticancer and Antimicrobial Agent, Prodigiosin, from Vibrio gazogenes PB1 and Its Identification by 1D and 2D NMR.

Prodigiosin is a secondary metabolite produced in several species of bacteria. It exhibits antimicrobial and anticancer properties. Methods for the extraction and identification of prodigiosin and their related derivatives from bacterial cultures typically depend on solvent-based extractions followed by NMR spectroscopy. The estuarine bacterium, V. gazogenes PB1, was previously shown to produce prodigiosin. This conclusion, however, was based on analytical data obtained from ultraviolet-visible absorption spectrophotometry and infrared spectroscopy. Complete dependence on these techniques would be considered inadequate for the accurate identification of the various members of the prodiginine family of compounds, which possess very similar chemical structures and near-identical optical properties. In this study, we extracted prodigiosin from a culture of Vibrio gazogenes PB1 cultivated in minimal media, and for the first time, confirmed the synthesis of prodigiosin Vibrio gazogenes PB1 using NMR techniques. The chemical structure was validated by 1H and 13C NMR spectroscopy, and further corroborated by 2D NMR, which included 1H-1H-gDQFCOSY, 1H-13C-gHSQC, and 1H-13C-gHMBC, as well as 1H-1H-homonuclear decoupling experiments. Based on this data, previous NMR spectral assignments of prodigiosin are reaffirmed and in some cases, corrected. The findings will be particularly relevant for experimental work relating to the use of V. gazogenes PB1 as a host for the synthesis of prodigiosin.

Synthesis, Anticancer Potential and Comprehensive Toxicity Studies of Novel Brominated Derivatives of Bacterial Biopigment Prodigiosin from Serratia marcescens ATCC 27117.

Prodigiosins (prodiginines) are a class of bacterial secondary metabolites with remarkable biological activities and color. In this study, optimized production, purification, and characterization of prodigiosin (PG) from easily accessible Serratia marcescens ATCC 27117 strain has been achieved to levels of 14 mg/L of culture within 24 h. Furthermore, environmentally friendly bromination of produced PG was used to afford both novel mono- and dibrominated derivatives of PG. PG and its Br derivatives showed anticancer potential with IC50 values range 0.62-17.00 µg/mL for all tested cancer cell lines and induction of apoptosis but low selectivity against healthy cell lines. All compounds did not affect Caenorhabditiselegans at concentrations up to 50 µg/mL. However, an improved toxicity profile of Br derivatives in comparison to parent PG was observed in vivo using zebrafish (Danio rerio) model system, when 10 µg/mL applied at 6 h post fertilization caused death rate of 100%, 30% and 0% by PG, PG-Br, and PG-Br2, respectively, which is a significant finding for further structural optimizations of bacterial prodigiosins. The drug-likeness of PG and its Br derivatives was examined, and the novel Br derivatives obey the Lipinski's "rule of five", with an exemption of being more lipophilic than PG, which still makes them good targets for further structural optimization.

Study on the Anticancer Activity of Prodigiosin from Variants of Serratia Marcescens QBN VTCC 910026.

Prodigiosin (Pg), a secondary metabolism produced by numerous bacterial species, is known as anticancer, antibacterial, antifungal, immunosuppressant, antioxidant, antimalarial properties. Pg has been tested for antitumor activity in many different cancer cell lines but studies in LU-1, KB cell lines, and tumor-bearing mice are still limited. In this study, Serratia marcescens QBN VTCC 910026 strain (GenBank: KX674054.1) was mutated using Ethyl Methanesulfonate (EMS) to increase the production of Pg. One strain known as EMS 5 was capable of increasing prodigiosin biosynthetic yield by 52% when compared to the wild-type strain. Red bacterial pigmented colonies containing Pg were collected from solid media, lysed with acetone, purified with toluene: ethyl acetate at a ratio of 9: 1 (v/v), and then used to evaluate the potential anticancer activity. The purity of Pg was confirmed using a high-performance liquid chromatography (HPLC) method which indicated a 98% rate. Pg chemical formula which was determined using 1H-NMR and 13C-NMR spectroscopy, confirmed as prodigiosin (Pg). Human breast cancer cell lines MCF-7, oropharyngeal cancer KB, and particularly lung cancer LU-1 in vitro were used to test the anticancer activity of purified Pg compound. It showed a strong inhibitory ability in all the cancer cell lines. Furthermore, the isolated Pg had capable of inhibiting tumor growth, the tumor volume decreased by 36.82%, after 28 days. The results indicated that the bacterial prodigiosin from variants Serratia marcescens QBN VTCC 910026 strain is an encouraging fragment suitable for therapeutic applications.

The prodigiosin change on the surface of Serratia marcescens detected by flow cytometry.

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.

Enhanced Large-Scale Production of Hahella chejuensis-Derived Prodigiosin and Evaluation of Its Bioactivity.

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.

Butylcycloheptylprodigiosin and undecylprodigiosin are potential photosensitizer candidates for photodynamic cancer therapy.

BACKGROUND: 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. METHODS AND RESULTS: 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). CONCLUSIONS: 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.

Bioprocessing of Marine Chitinous Wastes for the Production of Bioactive Prodigiosin.

Recently, microbial prodigiosin (PG) has received much attention due to its numerous beneficial applications. The aim of this study was to establish the bioprocessing of marine chitinous wastes (MCWs) for the cost-effective preparation of PG. Of the MCWs, demineralized shrimp shell powders (de-SSP) were found to be a potential source of carbon/nitrogen (C/N) for PG production by bacterial fermentation using Serratia marcescens strains. Further, PG scale-up production was investigated in a 15 L bioreactor system, and the highest yield (6200 mg/L) was achieved during fermentation using 5 L of a novel-designed culture broth that included 1.60% C/N sources (a de-SSP/casein ratio of 7/3), 0.02% K2SO4, and 0.05% K2HPO4, with an initial pH of 6-7. Fermentation was conducted in the dark at 27.5 °C for 8.0 h. This study was the first to report on the utilization of shrimp wastes for cost-effective, large-scale (5 L/pilot) PG production with high productivity (6200 mg/L) in a short cultivation time. The combination of 0.02% K2SO4 and 0.05% K2HPO4 was also found to be a novel salt composition that significantly enhanced PG yield. The red compound was purified and confirmed as PG after analyzing its HPLC profile, mass, and UV/vis spectra. The purified PG was then tested for its bioactivities and showed effective anticancer activities, moderated antioxidant activities, and novel anti-NO effects.

The different anion transport capability of prodiginine- and tambjamine-like molecules.

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.

Marine Actinomycetes-Derived Secondary Metabolites Overcome TRAIL-Resistance via the Intrinsic Pathway through Downregulation of Survivin and XIAP.

Resistance of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis represents the major hurdle to the clinical use of TRAIL or its derivatives. The discovery and development of lead compounds able to sensitize tumor cells to TRAIL-induced cell death is thus likely to overcome this limitation. We recently reported that marine actinomycetes' crude extracts could restore TRAIL sensitivity of the MDA-MB-231 resistant triple negative breast cancer cell line. We demonstrate in this study, that purified secondary metabolites originating from distinct marine actinomycetes (sharkquinone (1), resistomycin (2), undecylprodigiosin (3), butylcyclopentylprodigiosin (4), elloxizanone A (5) and B (6), carboxyexfoliazone (7), and exfoliazone (8)), alone, and in a concentration-dependent manner, induce killing in both MDA-MB-231 and HCT116 cell lines. Combined with TRAIL, these compounds displayed additive to synergistic apoptotic activity in the Jurkat, HCT116 and MDA-MB-231 cell lines. Mechanistically, these secondary metabolites induced and enhanced procaspase-10, -8, -9 and -3 activation leading to an increase in PARP and lamin A/C cleavage. Apoptosis induced by these compounds was blocked by the pan-caspase inhibitor QvD, but not by a deficiency in caspase-8, FADD or TRAIL agonist receptors. Activation of the intrinsic pathway, on the other hand, is likely to explain both their ability to trigger cell death and to restore sensitivity to TRAIL, as it was evidenced that these compounds could induce the downregulation of XIAP and survivin. Our data further highlight that compounds derived from marine sources may lead to novel anti-cancer drug discovery.

Degradable porous drug-loaded polymer scaffolds for localized cancer drug delivery and breast cell/tissue growth.

This paper presents the results of a combined experimental and analytical study of blended FDA-approved polymers [polylactic-co-glycolic acid (PLGA), polyethylene glycol (PEG) and polycaprolactone (PCL)] with the potential for sustained localized cancer drug release. Porous drug-loaded 3D degradable PLGA-PEG and PLGA-PCL scaffolds were fabricated using a multistage process that involved solvent casting and particulate leaching with lyophilization. The physicochemical properties including the mechanical, thermal and biostructural properties of the drug-loaded microporous scaffolds were characterized. The release of the encapsulated prodigiosin (PG) or paclitaxel (PTX) drug (from the drug-loaded polymer scaffolds) was also studied experimentally at human body temperature (37 °C) and hyperthermic temperatures (41 and 44 °C). These characteristic controlled and localized in vitro drug release from the properties of the microporous scaffold were analyzed using kinetics and thermodynamic models. Subsequently, normal breast cells (MCF-10A) were cultured for a 28-day period on the resulting 3D porous scaffolds in an effort to study the possible regrowth of normal breast tissue, following drug release. The effects of localized cancer drug release on breast cancer cells and normal breast cell proliferation are demonstrated for scenarios that are relevant to palliative breast tumor surgery for 16 weeks under in vivo conditions. Results from the in vitro drug release show a sustained anomalous (non-Fickian) drug release that best fits the Korsmeyer-Peppas (KP) kinetic model with a non-spontaneous thermodynamic process that leads to a massive decrease in breast cancer cell (MDA-MB-231) viability. Our findings from the animal suggest that localized drug release from drug-based 3D resorbable porous scaffolds can be used to eliminate/treat local recurred triple negative breast tumors and promote normal breast tissue regeneration after surgical resection.

Bacterial Pigment Prodigiosin Demonstrates a Unique Antiherpesvirus Activity That Is Mediated through Inhibition of Prosurvival Signal Transducers.

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.

Effects of oil substrate supplementation on production of prodigiosin by Serratia nematodiphila for dye-sensitized solar cell.

Bacterial pigments are potential substitute of chemical photosensitizer for dye-sensitized solar cell (DSSC) due to its non-toxic property and cost-effective production from microbial fermentation. Serratia nematodiphila YO1 was isolated from waterfall in Malaysia and identified using 16S ribosomal RNA. Characterization of the red pigment produced by the bacteria has confirmed the pigment as prodigiosin. Prodigiosin was produced from the fermentation of the bacteria in the presence of different oil substrates. Palm oil exhibited the best performance of cell growth and equivalent prodigiosin yield compared to olive oil and peanut oil. Prodigiosin produced with palm oil supplementation was 93 mg/l compared to 7.8 mg/l produced without supplementation, which recorded 11.9 times improvement. Specific growth rate of the cells improved 1.4 times when palm oil was supplemented in the medium. The prodigiosin pigment produced showed comparable performance as a DSSC sensitizer by displaying an open circuit voltage of 336.1 mV and a maximum short circuit current of 0.098 mV/cm2. This study stands a novelty in proving that the production of prodigiosin is favorable in the presence of palm oil substrate with high saturated fat content, which has not been studied before. This is also among the first bacterial prodigiosin tested as photosensitizer for DSSC application.

Recent advancements in high-level synthesis of the promising clinical drug, prodigiosin.

Prodigiosin, a red linear tripyrrole pigment and a member of the prodiginine family, is normally secreted by the human pathogen Serratia marcescens as a secondary metabolite. Studies on prodigiosin have received renewed attention as a result of reported immunosuppressive, antimicrobial and anticancer properties. High-level synthesis of prodigiosin and the bioengineering of strains to synthesise useful prodiginine derivatives have also been a subject of investigation. To exploit the potential use of prodigiosin as a clinical drug targeting bacteria or as a dye for textiles, high-level synthesis of prodigiosin is a prerequisite. This review presents an overview on the biosynthesis of prodigiosin from its natural host Serratia marcescens and through recombinant approaches as well as highlighting the beneficial properties of prodigiosin. We also discuss the prospect of adopting a synthetic biology approach for safe and cost-effective production of prodigiosin in a more industrially compliant surrogate host.