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Synthetic materials alternatives are crucial for reaching sustainable development goals and waste reduction. Biomaterials and biomolecules obtained through bacterial fermentation offer a viable solution. Double-layer active UV-blocking material composed of bacterial nanocellulose as an inner layer and poly(hydroxyoctanoic acid) containing prodigiosin as an active compound was produced by layer-by-layer deposition. This study referred the new material consisted of the three components produced in sustainable manner, by bacterial activity: bacterial bio-pigment prodigiosin, bacterial nanocellulose and poly(hydroytoctanoate) - biopolymer obtained by microbial fermentations. Prior the final double layer film was produced, PHO films containing different PG concentrations as a layer in charge of the bioactivity (0.2, 0.5 and 1 wt%) was casted and systematically characterized (FTIR, DSC, XRD, wettability, SEM, transparency, mechanical tests) to optimize their properties. The formulation with the best UV-blocking properties and less toxicity effect tested using MRC5 cells was chosen as an outer layer in double-layer films production. Water contact angle measurements confirmed that hydrophilic - hydrophobic double layer film was obtained with the improved mechanical properties in comparison to the native BNC. Migration test indicated release of PG in all tested media as a consequence of bilayer formulation, while the PG release from PHO in 10 % ethanol was not detected. All findings from the study suggested this activated, UV-blocking material as a candidate with excellent potential in packaging industry., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

As an important cellulose macromolecular-based material, cotton/polyamide and cotton/polyester fabrics are widely utilized in the textile and garment field due to their combination of the advantages of both cotton and synthetic fibers, such as excellent breathability, hygroscopicity, and abrasion performance. However, the synthetic dyes used in fabric coloration are derived from non-renewable resources, and the long-time dyeing procedure poses large pollution problems. Herein, microbial prodigiosins fermented by Serratia marcescens were employed for cotton/polyamide and cotton/polyester fabric dyeing and functionalizing. The results demonstrated that the prodigiosins suspension exhibited outstanding stability. Synthetic fibers contributed significantly to the overall color of fabrics and provided good dimensional stability and durability. In contrast, cotton fibers imparted relatively lighter color but played an essential role in enhancing the softness and comfort of fabrics. The dyed fabrics presented bright overall color light with good uniformity. Furthermore, the antibacterial rates of the dyed cotton/polyamide and cotton/polyester fabrics were 87.31 % and 89.70 %, respectively. The UPF values of the dyed cotton/polyamide and cotton/polyester fabrics were recorded as 52.3 and 93.5, respectively. This study provided a novel approach for cleaner functional dyeing of cotton/synthetic fiber two-component fabrics using prodigiosins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The negative environmental and social impacts of food waste accumulation can be mitigated by utilizing bio-refineries' approach where food waste is revalorized into high-value products, such as prodigiosin (PG), using microbial bioprocesses. The diverse biological activities of PG position it as a promising compound, but its high production cost and promiscuous bioactivity hinder its wide application. Metal ions can modulate the electronic properties of organic molecules, leading to novel mechanisms of action and increased target potency, while metal complex formation can improve the stability, solubility and bioavailability of the parent compound. The objectives of this study were optimizing PG production through bacterial fermentation using food waste, allowing good quantities of the pure natural product for further synthesizing and evaluating copper(II) and zinc(II) complexes with it. Their antimicrobial and anticancer activities were assessed, and their binding affinity toward biologically important molecules, bovine serum albumin (BSA) and DNA was investigated by fluorescence emission spectroscopy and molecular docking. The yield of 83.1 mg/L of pure PG was obtained when processed meat waste at 18 g/L was utilized as the sole fermentation substrate. The obtained complexes CuPG and ZnPG showed high binding affinity towards target site III of BSA, and molecular docking simulations highlighted the affinity of the compounds for DNA minor grooves.

The Prodiginins (PGs) natural pigments are secondary metabolites produced by a broad spectrum of gram-negative and gram-positive bacteria, notably by species within the Serratia and Streptomyces genera. These compounds exhibit diverse and potent biological activities, including anticancer, immunosuppressive, antimicrobial, antimalarial, and antiviral effects. Structurally, PGs share a common tripyrrolic core but possess variable side chains and undergo cyclization, resulting in structural diversity. Studies have investigated their antiproliferative effects on various cancer cell lines, with some PGs advancing to clinical trials for cancer treatment. This review aims to illuminate the molecular mechanisms underlying PG-induced apoptosis in cancer cells and explore the structure-activity relationships pertinent to their anticancer properties. Such insights may serve as a foundation for further research in anticancer drug development, potentially leading to the creation of novel, targeted therapies based on PGs or their derivatives., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Microbial life present in the marine environment has to be able to adapt to rapidly changing and often extreme conditions. This makes these organisms a putative source of commercially interesting compounds since adaptation provides different biochemical routes from those found in their terrestrial counterparts. In this work, the goal was the identification of a marine bacterium isolated from a sample taken at a shallow water hydrothermal vent and of its red product. Genomic, lipidomic, and biochemical approaches were used simultaneously, and the bacterium was identified as Serratia rubidaea . A high-throughput screening strategy was used to assess the best physico-chemical conditions permitting both cell growth and production of the red product. The fatty acid composition of the microbial cells was studied to assess adaptation at the lipid level under stressful conditions, whilst several state-of-the-art techniques, such as DSC, FTIR, NMR, and Ultra-High Resolution Qq-Time-of-Flight mass spectrometry, were used to characterize the structure of the pigment. We hypothesize that the pigment, which could be produced by the cells up to 62 °C, is prodigiosin linked to an aliphatic compound that acts as an anchor to keep it close to the cells in the marine environment.

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., (© 2021 International Union of Biochemistry and Molecular Biology, Inc.)

Bionanocomposites based on natural bioactive entities have gained importance due to their abundance; renewable and environmentally benign nature; and outstanding properties with applied perspective. Additionally, their formulation with biological molecules with antimicrobial, antioxidant, and anticancer activities has been produced nowadays. The present review details the state of the art and the importance of this pyrrolic compound produced by microorganisms, with interest towards Serratia marcescens , including production strategies at a laboratory level and scale-up to bioreactors. Promising results of its biological activity have been reported to date, and the advances and applications in bionanocomposites are the most recent strategy to potentiate and to obtain new carriers for the transport and controlled release of prodigiosin. Prodigiosin, a bioactive secondary metabolite, produced by Serratia marcescens , is an effective proapoptotic agent against bacterial and fungal strains as well as cancer cell lines. Furthermore, this molecule presents antioxidant activity, which makes it ideal for treating wounds and promoting the general improvement of the immune system. Likewise, some of the characteristics of prodigiosin, such as hydrophobicity, limit its use for medical and biotechnological applications; however, this can be overcome by using it as a component of a bionanocomposite. This review focuses on the chemistry and the structure of the bionanocomposites currently developed using biorenewable resources. Moreover, the work illuminates recent developments in pyrrole-based bionanocomposites, with special insight to its application in the medical area.

A rapid, efficient, and sensitive liquid chromatographic assay hyphenated to fluorometric detector (HPLC-FLD) was developed and validated for the determination of doxorubicin (DXR) and prodigiosin (PDG) in rat plasma. The sample pre-treatment involves a protein precipitation with acetonitrile with satisfying extraction efficiency (98% and 85% for DXR and PDG, respectively). The chromatographic separation was accomplished using stationary phase: Agilent Zorbax Eclipse plus-C18 analytical column (250 × 4.6 mm, 5 μm) and gradient eluting mobile phase of ammonium acetate (pH = 3), acetonitrile and methanol with programmed fluorescence detection. As the proposed method has been validated, it was subsequently implemented to evaluate DXR and PDG loaded on novel eco-friendly Casein nano drug delivery system after intravenous injection in healthy rats. A comparative pharmacokinetics' study was carried out in rats for DXR in free form, DXR alone entrapped in the nanomicelle and DXR with PDG entrapped in the nano micelle. After testing the differences in pharmacokinetic parameters of the different formulations using ANOVA, the results showed insignificant differences among the tested parameters. This indicates that the presented nanomicelle delivery system has succeeded to incorporate PDG and DXR in a hydrophilic, safe, and potent formulation. This novel nanomicelle has negligible effect on the distribution and elimination of DXR., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Prodigiosin is a tripyrrole red secondary metabolite synthesized by many microorganisms, including Serratia marcescens. In this study, we found that the deletion of the gene of sensor kinase CpxA dramatically decreased the prodigiosin production, while the deletion of the gene of the response regulator CpxR or both genes of CpxRA has no effect on prodigiosin production, the kinase function of CpxA is not essential for its regulation on prodigiosin production while the phosphorylation site of CpxR is required. We further demonstrated that the CpxA regulates the prodigiosin biosynthesis at the transcriptional level and the phosphatase activity of CpxA plays vital roles in the regulation of prodigiosin biosynthesis. Finally, we proposed that CpxR/A regulates the prodigiosin biosynthesis by negative control and the phosphorylation level of CpxR may determine the positive or negative control of the genes it regulated., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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% MgSO 4 , and 0.1% K 2 HPO 4 , 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.

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.

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 IC 50 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.

The acyl carrier protein (ACP) is an indispensable component of both fatty acid and polyketide synthases and is primarily responsible for delivering acyl intermediates to enzymatic partners. At present, increasing numbers of multidomain ACPs have been discovered with roles in molecular recognition of trans-acting enzymatic partners as well as increasing metabolic flux. Further structural information is required to provide insight into their function, yet to date, the only high-resolution structure of this class to be determined is that of the doublet ACP (two continuous ACP domains) from mupirocin synthase. Here we report the solution nuclear magnetic resonance (NMR) structure of the doublet ACP domains from PigH (PigH ACP 1 -ACP 2 ), which is an enzyme that catalyzes the formation of the bipyrrolic intermediate of prodigiosin, a potent anticancer compound with a variety of biological activities. The PigH ACP 1 -ACP 2 structure shows each ACP domain consists of three conserved helices connected by a linker that is partially restricted by interactions with the ACP 1 domain. Analysis of the holo (4'-phosphopantetheine, 4'-PP) form of PigH ACP 1 -ACP 2 by NMR revealed conformational exchange found predominantly in the ACP 2 domain reflecting the inherent plasticity of this ACP. Furthermore, ensemble models obtained from SAXS data reveal two distinct conformers, bent and extended, of both apo (unmodified) and holo PigH ACP 1 -ACP 2 mediated by the central linker. The bent conformer appears to be a result of linker-ACP 1 interactions detected by NMR and might be important for intradomain communication during the biosynthesis. These results provide new insights into the behavior of the interdomain linker of multiple ACP domains that may modulate protein-protein interactions. This is likely to become an increasingly important consideration for metabolic engineering in prodigiosin and other related biosynthetic pathways.

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This study aimed to establish the culture process for the cost-effective production of prodigiosin (PG) from demineralized crab shell powder (de-CSP), a fishery processing byproduct created via fermentation. Among the tested PG-producing strains, Serratia marcescens TNU02 was demonstrated to be the most active strain. Various ratios of protein/de-CSP were used as the sources of C/N for PG biosynthesis. The PG yield was significantly enhanced when the casein/de-CSP ratio was controlled in the range of 3/7 to 4/6. TNU02 produced PG with a high yield (5100 mg/L) in a 15 L bioreactor system containing 4.5 L of a newly-designed liquid medium containing 1.6% C/N source (protein/de-CSP ratio of 3/7), 0.02% (NH 4 ) 2 SO 4 , 0.1% K 2 HPO 4 , and an initial pH of 6.15, at 27 °C for 8 h in dark conditions. The red pigment was purified from the culture broth and then quantified as being PG by specific Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) and UV spectra analysis. The purified PG demonstrated moderate antioxidant and effective inhibition against four cancerous cell lines. Notably, this study was the first to report on using crab wastes for PG bioproduction with high-level productivity (5100 mg/L) in a large scale (4.5 L per pilot) in a short period of fermentation time (8 h). The salt compositions, including (NH 4 ) 2 SO 4 and K 2 HPO 4 , were also a novel finding for the enhancement of PG yield by S. marcescens in this report.

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., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest in this work., (Copyright © 2020. Published by Elsevier B.V.)

Prodiginines and tambjamines are related families of bioactive alkaloid natural products with pharmaceutical potential. Both compound families result from a convergent biosynthetic pathway ending in the condensation of a conserved bipyrrole core with a variable partner. This reaction is performed by unique condensation enzymes, and has the potential to be manipulated to produce new pyrrolic compounds. We have purified and reconstituted the in vitro activity of the condensation enzymes PigC and TamQ from Pseudoalteromonas sp., which are involved, respectively, in the prodiginine and tambjamine biosynthetic pathways. Kinetic analysis confirmed a Uni Uni Bi Uni ping-pong reaction sequence with competitive and uncompetitive substrate inhibition for PigC and TamQ respectively. The kinetic parameters of each enzyme provide insight into their differing substrate scope, and suggest that TamQ may have evolved a wide substrate tolerance that can be used for the production of novel prodiginines and tambjamines., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Ion mobility spectrometry was utilized to corroborate the identity of streptorubin B ( 2 ) as the natural product produced by Streptomyces coelicolor . Natural product 2 was initially assigned as butylcycloheptylprodigiosin ( 3 ), and only relatively recently was this assignment clarified. We present additional evidence of this assignment by comparing collisional cross sections (Ω) of synthetic standards of 2 , 3 , and metacycloprodigiosin ( 4 ) to the cyclic prodiginine produced by S. coelicolor . Calculated theoretical Ω values demonstrate that cyclic prodiginines could be identified without standards. This work highlights ion mobility as an efficient tool for the dereplication of natural products.

Marine chitins (MC) have been utilized for the production of vast array of bioactive products, including chitooligomers, chitinase, chitosanase, antioxidants, anti-NO, and antidiabetic compounds. The aim of this study is the bioprocessing of MC into a potent anticancer compound, prodigiosin (PG), via microbial fermentation. This bioactive compound was produced by Serratia marcescens TKU011 with the highest yield of 4.62 mg/mL at the optimal conditions of liquid medium with initial pH of 5.65-6.15 containing 1% α-chitin, 0.6% casein, 0.05% K 2 HPO 4 , and 0.1% CaSO 4 . Fermentation was kept at 25 °C for 2 d. Notably, α-chitin was newly investigated as the major potential material for PG production via fermentation; the salt CaSO 4 was also found to play the key role in the enhancement of PG yield of Serratia marcescens fermentation for the first time. PG was qualified and identified based on specific UV, MALDI-TOF MS analysis. In the biological activity tests, purified PG demonstrated potent anticancer activities against A549, Hep G2, MCF-7, and WiDr with the IC 50 values of 0.06, 0.04, 0.04, and 0.2 µg/mL, respectively. Mytomycin C, a commercial anti-cancer compound was also tested for comparison purpose, showing weaker activity with the IC 50 values of 0.11, 0.1, 0.14, and 0.15 µg/mL, respectively. As such, purified PG displayed higher 2.75-fold, 1.67-fold, and 3.25-fold efficacy than Mytomycin C against MCF-7, A549, and Hep G2, respectively. The results suggest that marine chitins are valuable sources for production of prodigiosin, a potential candidate for cancer drugs.

The genus Serratia is a predominantly unexplored source of antimicrobial secondary metabolites. The aim of the current study was thus to isolate and evaluate the antimicrobial properties of biosurfactants produced by Serratia species. Forty-nine (n = 34 pigmented; n = 15 non-pigmented) biosurfactant producing Serratia strains were isolated from environmental sources and selected isolates (n = 11 pigmented; n = 11 non-pigmented) were identified as Serratia marcescens using molecular typing. The swrW gene (serrawettin W1 synthetase) was detected in all the screened pigmented strains and one non-pigmented strain and primers were designed for the detection of the swrA gene (non-ribosomal serrawettin W2 synthetase), which was detected in nine non-pigmented strains. Crude extracts obtained from S. marcescens P1, NP1 and NP2 were chemically characterised using ultra-performance liquid chromatography coupled to electrospray ionisation mass spectrometry (UPLC-ESI-MS), which revealed that P1 produced serrawettin W1 homologues and prodigiosin, while NP1 produced serrawettin W1 homologues and glucosamine derivative A. In contrast, serrawettin W2 analogues were predominantly identified in the crude extract obtained from S. marcescens NP2. Both P1 and NP1 crude extracts displayed broad-spectrum antimicrobial activity against clinical, food and environmental pathogens, such as multidrug-resistant Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus and Cryptococcus neoformans. In contrast, the NP2 crude extract displayed antibacterial activity against a limited range of pathogenic and opportunistic pathogens. The serrawettin W1 homologues, in combination with prodigiosin and glucosamine derivatives, produced by pigmented and non-pigmented S. marcescens strains, could thus potentially be employed as broad-spectrum therapeutic agents against multidrug-resistant bacterial and fungal pathogens., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

The available and effective therapeutic means to treat choriocarcinoma is seriously lacking, mainly due to the toxic effects caused by chemotherapy and radiotherapy. Accordingly, we developed a method for targeting delivery of chemotherapeutical drugs only to cancer cells, not normal cells, in vivo , by using a synthetic placental chondroitin sulfate (CSA)-binding peptide (plCSA-BP) derived from malarial protein VAR2CSA. A 28 amino acids placental CSA-binding peptide (plCSA-BP) from the VAR2CSA was synthesized as a guiding peptide for tumor-targeting delivery, dendrigraft poly-L-lysines (DGL) was modified with plCSA-BP and served as a novel targeted delivery carrier. Choriocarcinoma was selected to test the effect of targeted delivery carrier, and prodigiosin isolated from Serratia marcescens subsp. lawsoniana was selected as a chemotherapeutical drug and encapsulated in the DGL modified by the plCSA-BP nanoparticles (DGL/CSA-PNPs). DGL/CSA-PNPs had a sustained slow-release feature at pH 7.4, which could specifically bind to the JEG3 cells and exhibited better anticancer activity than that of the controls. The DGL/CSA-PNPs induced the apoptosis of JEG3 cells through caspase-3 and the P53 signaling pathway. DGL/CSA-PNPs can be used as an excellent targeted delivery carrier for anticancer drugs, and the prodigiosin could be an alternative chemotherapeutical drug for choriocarcinoma.

Synthetic anion transporters that facilitate transmembrane H + /Cl - symport (cotransport) have anti-cancer potential due to their ability to neutralize pH gradients and inhibit autophagy in cells. However, compared to the natural product prodigiosin, synthetic anion transporters have low-to-modest H + /Cl - symport activity and their mechanism of action remains less well understood. We report a chloride-selective tetraurea macrocycle that has a record-high H + /Cl - symport activity similar to that of prodigiosin and most importantly demonstrates unprecedented voltage-switchable transport properties that are linked to the lack of uniport activity. By studying the anion binding affinity and transport mechanisms of four other anion transporters, we show that the lack of uniport and voltage-dependent H + /Cl - symport originate from strong binding to phospholipid headgroups that hampers the diffusion of the free transporters through the membrane, leading to an unusual H + /Cl - symport mechanism that involves only charged species. Our work provides important mechanistic insights into different classes of anion transporters and a new approach to achieve voltage-switchability in artificial membrane transport systems., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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 Ca 2+ homeostasis and increase the intracellular concentration of Ca 2+ 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.

Identification of RNA-interacting pharmacophores could provide chemical probes and, potentially, small molecules for RNA-based therapeutics. Using a high-throughput differential scanning fluorimetry assay, we identified small-molecule natural products with the capacity to bind the discrete stem-looped structure of pre-miR-21. The most potent compound identified was a prodiginine-type compound, butylcycloheptyl prodiginine (bPGN), with the ability to inhibit Dicer-mediated processing of pre-miR-21 in vitro and in cells. Time-dependent RT-qPCR, western blot, and transcriptomic analyses showed modulation of miR-21 expression and its target genes such as PDCD4 and PTEN upon treatment with bPGN, supporting on-target inhibition. Consequently, inhibition of cellular proliferation in HCT-116 colorectal cancer cells was also observed when treated with bPGN. The discovery that bPGN can bind and modulate the expression of regulatory RNAs such as miR-21 helps set the stage for further development of this class of natural product as a molecular probe or therapeutic agent against miRNA-dependent diseases., (Published by Elsevier Ltd.)

This paper presents the anomalous release kinetics of a cancer drug (prodigiosin) frompoly-n-isopropyl-acrylamide (P(NIPA))-based gels. The release exponents, n, which correspond to the drug release mechanisms, were found to be between 0.41 and 1.40. This is within a range that include Fickian case I (n = 0.45) and non-Fickian diffusion (case II) (n > 0.45) for cylindrical drug-loaded structures. The results, however, suggest that the release exponents, n, correspond mostly to anomalous case II and super case II transport mechanics with sigmoidal characteristics. The drug release kinetics of the P(NIPA)-based hydrogels are well described by bi-dose functions. The observed drug release behavour is related to the porosity of the hydrogels, which can be controlled by cross-linking and copolymerization with acrylamide, which also improves the hydrophilicity of the gels. The paper also presents the effects of cancer drug release on cell survival (%), as well as the cell metabolic activities of treated cells and non-treated cells. The implications of the results are discussed for the development of implantable thermosensitive gels for the controlled release of drugs for localized cancer treatment.

Prodigiosin is an intensely red pigment comprising three pyrroles. The biosynthetic pathway includes a two-step proline oxidation catalyzed by phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PigA), with flavin adenine dinucleotide (FAD) as its cofactor. The enzyme is crystallized in the apo form and in complex with FAD and proline. As an acyl coenzyme A dehydrogenase (ACAD) family member, the protein folds into a β-sheet flanked by two α-helical domains. PigA forms a tetramer, which is consistent with analytical ultracentrifugation results. FAD binds to PigA in a similar way to that in the other enzymes of the ACAD family. The variable conformations of loop β4-β5 and helix αG correlate well with the structural flexibility required for substrate entrance to the Re side of FAD. Modeling with PigG, the acyl carrier protein, suggests a reasonable mode of interaction with PigA. The structure helps to explain the proline oxidation mechanism, in which Glu244 plays a central role by abstracting the substrate protons. It also reveals a plausible pocket for oxygen binding to the Si side of FAD., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: In Streptomyces, understanding the switch from primary to secondary metabolism is important for maximizing the production of secondary metabolites such as antibiotics, as well as for optimizing recombinant glycoprotein production. Differences in Streptomyces lividans bacterial aggregation as well as recombinant glycoprotein production and O-mannosylation have been reported due to modifications in the shake flask design. We hypothetized that such differences are related to the metabolic switch that occurs under oxygen-limiting conditions in the cultures., Results: Shake flask design was found to affect undecylprodigiosin (RED, a marker of secondary metabolism) production; the RED yield was 12 and 385 times greater in conventional normal Erlenmeyer flasks (NF) than in baffled flasks (BF) and coiled flasks (CF), respectively. In addition, oxygen transfer rates (OTR) and carbon dioxide transfer rates were almost 15 times greater in cultures in CF and BF as compared with those in NF. Based on these data, we obtained respiration quotients (RQ) consistent with aerobic metabolism for CF and BF, but an RQ suggestive of anaerobic metabolism for NF., Conclusion: Although the metabolic switch is usually related to limitations in phosphate and nitrogen in Streptomyces sp., our results reveal that it can also be activated by low OTR, dramatically affecting recombinant glycoprotein production and O-mannosylation and increasing RED synthesis in the process.

Covering: up to the end of 2017 The roles played by Rieske non-heme iron-dependent oxygenases in natural product biosynthesis are reviewed, with particular focus on experimentally characterised examples. Enzymes belonging to this class are known to catalyse a range of transformations, including oxidative carbocyclisation, N-oxygenation, C-hydroxylation and C-C desaturation. Examples of such enzymes that have yet to be experimentally investigated are also briefly described and their likely functions are discussed.

The search for new chemotherapeutics unaffected by efflux pumps would significantly increase life expectancy in patients with malignant cancers. In this study, butylcycloheptylprodigiosin and undecylprodigiosin were HPLC-purified and verified, using nuclear magnetic resonance spectroscopy. Cell cytotoxicity and transportation kinetics on multiple-drug resistance (MDR) cells were evaluated. Daunorubicin and butylcycloheptylprodigiosin were less toxic in the MDR1 overexpressing line, but undecylprodigiosin revealed potent toxicity toward MDR1 and BCRP expressing malignant cells. There was no noticeable change in MDR1 and BCRP transcripts during 3 days of treatment with prodiginines. While daunorubicin and mitoxantrone uptake from the cell environment significantly decreased with increasing multidrug resistance up to 46% and 62%, respectively, the accumulation of undecylprodigiosin and to a lesser extent butylcycloheptylprodigiosin in the resistance cells occurred cell- and dose-dependently via a passive diffusion process and were almost equally sensitive to the parent lines. The efflux of xenobiotics commenced immediately with different kinetics in various cells. A greater amount of daunorubicin and mitoxantrone were rapidly thrown out of their corresponding MDR cells in the absence of the specific inhibitor (3.01 and 1.81 dF/min, respectively) and represented functional efflux pumps. MDR pumps did not apparently influence undecylprodigiosin efflux patterns; but butylcycloheptylprodigiosin was partially removed from EPG85.257RDB cells at the rate of 2.66 and 1.41 dF/min in the absence and presence of verapamil, respectively.

The photo-induced cytotoxicity of prodigiosenes is reported. One prodigiosene represents a synthetic analogue of the natural product prodigiosin, and two are conjugated to molecules that target the estrogen receptor (ER). A comparison of incubation and irradiation frameworks for the three prodigiosenes is reported, with activity against ER- and ER+ lines explored. Furthermore, the ability of the three prodigiosenes to photosensitise the production of singlet oxygen is demonstrated, shedding mechanistic light onto possible photodynamic therapeutic effects of this class of tripyrroles.

Symbiotic bacteria can produce secondary metabolites and volatile compounds that contribute to amphibian skin defense. Some of these symbionts have been used as probiotics to treat or prevent the emerging disease chytridiomycosis. We examined 20 amphibian cutaneous bacteria for the production of prodigiosin or violacein, brightly colored defense compounds that pigment the bacteria and have characteristic spectroscopic properties making them readily detectable, and evaluated the antifungal activity of these compounds. We detected violacein from all six isolates of Janthinobacterium lividum on frogs from the USA, Switzerland, and on captive frogs originally from Panama. We detected prodigiosin from five isolates of Serratia plymuthica or S. marcescens, but not from four isolates of S. fonticola or S. liquefaciens. All J. lividum isolates produced violacein when visibly purple, while prodigiosin was only detected on visibly red Serratia isolates. When applied to cultures of chytrid fungi Batrachochytrium dendrobatidis (Bd) and B. salamandrivorans (Bsal), prodigiosin caused significant growth inhibition, with minimal inhibitory concentrations (MIC) of 10 and 50 μM, respectively. Violacein showed a MIC of 15 μM against both fungi and was slightly more active against Bsal than Bd at lower concentrations. Although neither violacein nor prodigiosin showed aerosol activity and is not considered a volatile organic compound (VOC), J. lividum and several Serratia isolates did produce antifungal VOCs. White Serratia isolates with undetectable prodigiosin levels could still inhibit Bd growth indicating additional antifungal compounds in their chemical arsenals. Similarly, J. lividum can produce antifungal compounds such as indole-3-carboxaldehyde in addition to violacein, and isolates are not always purple, or turn purple under certain growth conditions. When Serratia isolates were grown in the presence of cell-free supernatant (CFS) from the fungi, CFS from Bd inhibited growth of the prodigiosin-producing isolates, perhaps indicative of an evolutionary arms race; Bsal CFS did not inhibit bacterial growth. In contrast, growth of one J. lividum isolate was facilitated by CFS from both fungi. Isolates that grow and continue to produce antifungal compounds in the presence of pathogens may represent promising probiotics for amphibians infected or at risk of chytridiomycosis. In a global analysis, 89% of tested Serratia isolates and 82% of J. lividum isolates were capable of inhibiting Bd and these have been reported from anurans and caudates from five continents, indicating their widespread distribution and potential for host benefit.

Urinary tract infections are the utmost common bacterial infections caused by Proteus mirabilis, Pseudomonas aeruginosa, Escherichia coli, and Serratia marcescens. These uropathogens resist the action of several antibiotics due to their ability to form biofilms. Most of these bacterial pathogens use the quorum sensing (QS) machinery to co-ordinate their cells and regulate several virulence factors and biofilm formation. On the other hand, the anti-quorum sensing (anti-QS) and antibiofilm potential of silver nanoparticles have been well reported against certain bacterial pathogens, but to the best of our knowledge, no report is available against the pathogenicity of uropathogens in particular S. marcescens and P. mirabilis. Therefore, the present study is primarily focused on the anti-QS and antibiofilm potential of Piper betle-based synthesized silver nanoparticles (PbAgNPs) against S. marcescens and P. mirabilis. Initially, the silver nanoparticles were synthesized by the aqueous extract of P. betle and characterized by UV-absorbance spectroscopy, XRD, FT-IR, SEM, TEM, and DLS. The synthesized silver nanoparticles were assessed for their anti-QS activity and the obtained results revealed that the PbAgNPs inhibited the QS-mediated virulence factors such as prodigiosin, protease, biofilm formation, exopolysaccharides and hydrophobicity productions in uropathogens. The gene expression analysis divulged the downregulation of fimA, fimC, flhD, and bsmB genes in S. marcescens and flhB, flhD, and rsbA genes in P. mirabilis, respectively. The in vivo Caenorhabditis elegans assays revealed the non-toxic and anti-adherence efficiency of PbAgNPs. Furthermore, the non-toxic effect of PbAgNPs was also confirmed through peripheral blood mononuclear cells and normal lung epithelial cells. Therefore, the contemporary study demonstrates the use of PbAgNPs as a possible alternative toward conventional antibiotics in controlling QS and biofilm-related uropathogen infections.

Anion selective ionophores, anionophores, are small molecules capable of facilitating the transmembrane transport of anions. Inspired in the structure of natural product prodigiosin, four novel anionophores 1a-d, including a 1,2,3-triazole group, were prepared. These compounds proved highly efficient anion exchangers in model phospholipid liposomes. The changes in the hydrogen bond cleft modified the anion transport selectivity exhibited by these compounds compared to prodigiosin and suppressed the characteristic high toxicity of the natural product. Their activity as anionophores in living cells was studied and chloride efflux and iodine influx from living cells mediated by these derivatives was demonstrated. These compounds were shown to permeabilize cellular membranes to halides with efficiencies close to the natural anion channel CFTR at doses that do not compromise cellular viability. Remarkably, optimal transport efficiency was measured in the presence of pH gradients mimicking those found in the airway epithelia of Cystic Fibrosis patients. These results support the viability of developing small molecule anionophores as anion channel protein surrogates with potential applications in the treatment of conditions such as Cystic Fibrosis derived from the malfunction of natural anion transport mechanisms.

Alphaproteobacterium strain MOLA1416, related to Mycoplana ramosa DSM 7292 and Chelativorans intermedius CC-MHSW-5 (93.6% 16S rRNA sequence identity) was isolated from the marine lichen, Lichina pygmaea and its chemical composition was characterized by a metabolomic network analysis using LC-MS/MS data. Twenty-five putative different compounds were revealed using a dereplication workflow based on MS/MS signatures available through GNPS (https://gnps.ucsd.edu/). In total, ten chemical families were highlighted including isocoumarins, macrolactones, erythrinan alkaloids, prodiginines, isoflavones, cyclohexane-diones, sterols, diketopiperazines, amino-acids and most likely glucocorticoids. Among those compounds, two known metabolites (13 and 26) were isolated and structurally identified and metabolite 26 showed a high cytotoxic activity against B16 melanoma cell lines with an IC 50 0.6 ± 0.07 μg/mL., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In present investigation, two glucose based smart tumor-targeted drug delivery systems coupled with enzyme-sensitive release strategy are introduced. Magnetic nanoparticles (Fe 3 O 4 ) were grafted with carboxymethyl chitosan (CS) and β-cyclodextrin (β-CD) as carriers. Prodigiosin (PG) was used as the model anti-tumor drug, targeting aggressive tumor cells. The morphology, properties and composition and grafting process were characterized by transmission electron microscope (TEM), Fourier transform infrared spectroscopy (FT-IR), vibration sample magnetometer (VSM), X-ray diffraction (XRD) analysis. The results revealed that the core crystal size of the nanoparticles synthesized were 14.2±2.1 and 9.8±1.4nm for β-CD and CS-MNPs respectively when measured using TEM; while dynamic light scattering (DLS) gave diameters of 121.1 and 38.2nm. The saturation magnetization (Ms) of bare magnetic nanoparticles is 50.10emucm -3 , while modification with β-CD and CS gave values of 37.48 and 65.01emucm -3 , respectively. The anticancer compound, prodigiosin (PG) was loaded into the NPs with an encapsulation efficiency of approximately 81% for the β-CD-MNPs, and 92% for the CS-MNPs. This translates to a drug loading capacity of 56.17 and 59.17mg/100mg MNPs, respectively. Measurement of in vitro release of prodigiosin from the loaded nanocarriers in the presence of the hydrolytic enzymes, alpha-amylase and chitosanase showed that 58.1 and 44.6% of the drug was released after one-hour of incubation. Cytotoxicity studies of PG-loaded nanocarriers on two cancer cell lines, MCF-7 and HepG2, and on a non-cancerous control, NIH/3T3 cells, revealed that the drug loaded nanoparticles had greater efficacy on the cancer cell lines. The selective index (SI) for free PG on MCF-7 and HepG2 cells was 1.54 and 4.42 respectively. This parameter was reduced for PG-loaded β-CD-MNPs to 1.27 and 1.85, while the SI for CS-MNPs improved considerably to 7.03 on MCF-7 cells. Complementary studies by fluorescence and confocal microscopy and flow cytometry confirm specific targeting of the nanocarriers to the cancer cells. The results suggest that CS-MNPs have higher potency and are better able to target the prodigiosin toxicity effect on cancerous cells than β-CD-MNPs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Owing to the importance of endophytes, current research was aimed to purify the secondary metabolites from targeted source. Ferula sumbul, a lipophilic extract of the endophyte was prepared in 10% methanol and partitioned with ethyl acetate and bioassay guided isolation was carried using standard protocols against bacterial, fungal and cancer cells. The active fractions consisted of three new metabolites (2-methyl-3-nonyl prodiginine, Bis (2-ethylhexyl) phthalate, and a meroterpenoid, Preaustinoid A). Their structures were confirmed with LCMS/MS. The purified metabolites showed valuable results against tested activities which concluded that these compounds have great potential and these may be applicable to textile (dyeing), pharmaceutical (drug, infectious agents) and food (preservatives) industries. This study reveals the potential of E. nigrum as an important source of bioactive compounds including 2-methyl-3-nonyl prodiginine, Bis (2-ethylhexyl) phthalate, and Preaustinoid A. This is first report of isolation of prodiginines as well as meroterpenoid and Bis (2-ethylhexyl) phthalate from Epicoccum nigrum., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

This paper explores the adhesion of biosynthesized gold nanoparticles (AuNPs) and gold (Au) nanoparticle/prodigiosin (PG) drug nanoparticles to breast cancer cells (MDA-MB-231 cells). The AuNPs were synthesized in a record time (less than 30 s) from Nauclea latifolia leaf extracts, while the PG was produced via bacterial synthesis with Serratia marcescens sp. The size distributions and shapes of the resulting AuNPs were characterized using transmission electron microscopy (TEM), while the resulting hydrodynamic diameters and polydispersity indices were studied using dynamic light scattering (DLS). Atomic Force Microscopy (AFM) was used to study the adhesion between the synthesized gold nanoparticles (AuNPs)/LHRH-conjugated AuNPs and triple negative breast cancer cells (MDA-MB-231 cells), as well as the adhesion between LHRH-conjugated AuNP/PG drug and MDA-MB-231 breast cancer cells. The adhesion forces between LHRH-conjugated AuNPs and breast cancer cells are shown to be five times greater than those between AuNPs and normal breast cells. The increase in adhesion is shown to be due to the over-expression of LHRH receptors on the surfaces of MDA-MB-231 breast cancer cells, which was revealed by confocal immuno-fluorescence microscopy. The implications of the results are then discussed for the selective and specific targeting and treatment of triple negative breast cancer.

We report the synthesis of the first click-appended prodigiosene conjugates. Four prodigiosene conjugates of estradiol functionalised at the 7α-position were prepared, as were three prodigiosene conjugates of tamoxifen. The coupling between a prodigiosene and an 11-hydroxy estradiol derivative via an ether linkage was investigated, as was the 11- and 7-functionalisation of the estradiol core. The robustness of estradiol protecting groups was severely challenged by reactions typically used to equip such frameworks for 11- and 7-functionalisation. Specifically, and important to synthesis involving estradiol, TBS, TMS and THP are not useful protecting groups for the functionalisation of this core. When the chemical features of the therapeutic agent limit the choice of protecting group (in this case, prodigiosenes bearing aryl, NH, alkenyl and ester groups), click chemistry becomes an attractive synthetic strategy. The anti-cancer activity of the seven click prodigiosene conjugates was evaluated.

A novel bifunctional enzyme, MarH, has been identified, and its key functional role in the marineosin biosynthesis successfully probed. MarH catalyzes (1) a condensation step between 4-methoxy-2,2'-bipyrrole-5-carboxaldehyde (MBC) and 2-undecylpyrrole (UP) to form undecylprodiginine (UPG) and (2) hydroxylation of the alkyl chain of UPG to form the (S)-23-hydroxyundecylprodiginine (HUPG), which is essential for MarG catalyzed bicyclization toward the formation of an unusual spiro-tetrahydropyran-aminal ring of marineosins. The final enigmatic steps in the marineosin biosynthesis have now been deciphered.

Synthetic fatliquors are useful as a fatliquoring agent, flotation agent and emulsifying agent in a wide range of industrial applications such as leather, pharmacy and farm chemicals. These fatliquors remain recalcitrant to natural biota in existing treatment plants. In the present study, the isolated microaerophilic Serratia sp. HA1 strain CSMB3 is capable of utilizing structurally different fatliquors as the sole substrate for their growth under microaerobic conditions. Degradation of vegetable fatliquors was observed from 95 to 97% in terms of lipids, with the production of lipase at 72 h. Degradation of synthetic fatliquors was observed in terms of chemical oxygen demand from 85% to a minimum of 25%. It is in the order of sulfited/sulfated fatliquors > sulfochlorinated fatliquors > chlorinated fatliquors. A thin layer chromatography chromatogram confirmed the degradation of non polar fatliquor to polar compounds. Production of the red pigment prodigiosin in synthetic fatliquors enhanced the growth of the isolate. Fourier transform infrared spectroscopy (FTIR) confirmed the bioremediation of sulfochlorinated fatliquor into lipids and fatty acids and gas chromatography-mass spectrometry (GC-MS) results confirmed that alcohols and esters are the final end products. Thus the isolated strain CSMB3 may be used in the treatment of wastewaters containing vegetable and synthetic fatliquors.

The encapsulation of drugs in polymeric materials has brought opportunities to the targeted delivery of chemotherapeutic agents. These polymeric delivery systems are capable of maximizing the therapeutic activity, as well as reducing the side effects of anti-cancer agents. Prodigiosin, a secondary metabolite extracted from the bacteria, Serratia marcescens, exhibits anti-cancer properties. Prodigiosin-loaded chitosan microspheres were prepared via water-in-oil (w/o) emulsion technique, using glutaraldehyde as a cross-linker. The morphologies of the microspheres were studied using scanning electron microscopy. The average sizes of the microspheres were between 40μm and 60μm, while the percentage yields ranged from 42±2% to 55.5±3%. The resulting encapsulation efficiencies were between 66.7±3% and 90±4%. The in-vitro drug release from the microspheres was characterized by zeroth order, first order and Higuchi and Korsmeyer-Peppas models., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Here, we report the first total synthesis of hybrubin A, a bipyrrole tetramic acid alkaloid representing a new carbon framework derived from convergent (truncated red cluster and exogenous hbn cluster) biosynthetic pathways. A highly convergent synthesis was developed, employing 4-methoxy-1,5-dihydro-2H-pyrrol-2-one (13) as a single starting material to provide hybrubin A in three steps from 13 and 20.8% overall yield. As no biological activity was prescribed to hybrubin A except for a lack of cytotoxicity, we further profiled this unique alkaloid across panels of discrete molecular targets. Interestingly, hybrubin A was found to be a ligand for a variety of GPCRs with a propensity for potent binding across therapeutically relevant adenosine receptors (A 1 , A 2a , and A 3 ) as well as a potent activity at a kinase, FLT3. This pattern of biological activity is distinct from other related prodigiosin natural and unnatural products and is even more intriguing in the absence of cytotoxicity.

Prodigiosin (PG) is a bioactive compound produced by several bacterial species. Currently, many technologies are being developed for the production of PG by fermentation processes. However, new challenges are being faced with regard to the production of PG in terms of the recovery and purification steps, owing to the labile nature of PG molecules and the cost of the purification steps. Conventional methods have limitations due to high cost, low reusability, and health hazards. Hence, the present investigation was focused on the development of surface-functionalized magnetic iron oxide ([Fe3O4]F) for solvent-free extraction of bioactive PG from the bacterial fermented medium. Fe3O4 was functionalized with diethanolamine and characterized by FT-IR, diffuse reflectance spectroscopy, thermogravimetric analysis, scanning electron microscopy, and confocal microscopy. The various process parameters, such as contact time, temperature, pH, and mass of Fe3O4, were optimized for the extraction of PG using functionalized Fe3O4. Instrumental analyses confirmed that the PG molecules were cross-linked with functional groups on [Fe3O4]F through van der Waals forces of attraction. PG extracted through Fe3O4 or [Fe3O4]F was separated from the fermentation medium by applying an external electromagnetic field and regenerated for successive reuse cycles. The purity of the extracted PG was characterized by high-performance liquid chromatography, FT-IR, and UV-visible spectroscopy. The iron oxide-diethanolamine-PG cross-linked ([Fe3O4]F-PG) composite matrix effectively deactivates harmful fouling by cyanobacterial growth in water-treatment plants. The present investigation provides the possibility of solvent-free extraction of bacterial bioactive PG from a fermented medium using functionalized magnetic iron oxide.

This paper presents the synthesis and physicochemical characterization of biodegradable poly (d,l-lactide-co-glycolide) (PLGA)-based microparticles that are loaded with bacterial-synthesized prodigiosin drug obtained from Serratia marcescens subsp. Marcescens bacteria for controlled anticancer drug delivery. The micron-sized particles were loaded with anticancer drugs [prodigiosin (PG) and paclitaxel (PTX) control] using a single-emulsion solvent evaporation technique. The encapsulation was done in the presence of PLGA (as a polymer matrix) and poly-(vinyl alcohol) (PVA) (as an emulsifier). The effects of processing conditions (on the particle size and morphology) are investigated along with the drug release kinetics and drug-loaded microparticle degradation kinetics. The localization and apoptosis induction by prodigiosin in breast cancer cells is also elucidated along with the reduction in cell viability due to prodigiosin release. The implication of this study is for the potential application of prodigiosin PLGA-loaded microparticles for controlled delivery of cancer drug and treatment to prevent the regrowth or locoregional recurrence, following surgical resection of triple negative breast tumor., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Human serum albumin (HSA) and bovine β-lactoglobulin (β-Lg) are both introduced as blood and oral carrier scaffolds with high affinity for a wide range of pharmaceutical compounds. Prodigiosin, a natural three pyrrolic compound produced by Serratia marcescens, exhibits many pharmaceutical properties associated with health benefits. In the present study, the interaction of prodigiosin with HSA and β-Lg was investigated using fluorescence spectroscopy, circular dichroism (CD) and computational docking. Prodigiosin interacts with the Sudlow's site I of HSA and the calyx of β-Lg with association constant of 4.41 × 10(4) and 1.99 × 10(4) M(-1) to form 1:1 and 2:3 complexes at 300K, respectively. The results indicated that binding of prodigiosin to HSA and β-Lg caused strong fluorescence quenching of both proteins through static quenching mechanism. Electrostatic and hydrophobic interactions are the major forces in the stability of PG-HSA complex with enthalpy- and entropy-driving mode, although the formation of prodigiosin-β-Lg complex is entropy-driven hydrophobic associations. CD spectra showed slight conformational changes in both proteins due to the binding of prodigiosin. Moreover, the ligand displacement assay, pH-dependent interaction and protein-ligand docking study confirmed that the prodigiosin binds to residues located in the subdomain IIA and IIIA of HSA and central calyx of β-Lg., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Heterologous expression of bacterial artificial chromosome (BAC) clones from the genomic library of Streptomyces variabilis Snt24 in Streptomyces lividans SBT5 which carried a truncated undecylprodigiosin biosynthetic gene cluster led to the identification of hybrubins A-C. The hybrubins represent a new carbon skeleton in which a tetramic acid moiety is fused to a 2,2'-dipyrrole building block. Gene knockout experiments confirmed that hybrubins are derived from two convergent biosynthetic pathways including the remaining genomic red genes of S. lividans SBT5 as well as the BAC encoded hbn genes for the production of 5-ethylidenetetramic acid. A possible biosynthetic pathway was also proposed.

We present the results of swelling experiments on poly(N-isopropylacrylamide) P(NIPA)-based hydrogels. The swelling characteristics of P(NIPA)-based homo-polymer and P(NIPA)-based co-polymers with Acrylamide (AM) and Butyl Methacrylate (BMA), were studied using weight gain experiments. The swelling due to the uptake of biosynthesized cancer drug, prodigiosin (PG), was compared to swelling in controlled environments (distilled water (DW), paclitaxel™ (PT) and bromophenol blue (BB)). PG was synthesized with Serratia marcescens (SM) subsp. marcescens bacteria. The mechanisms of drug diffusion and swelling of P(NIPA)-based hydrogels are also elucidated along with characterizing the heterogeneous porous structure of the P(NIPA)-based hydrogels. High Performance Liquefied Chromatography (HPLC) analysis revealed the purity of the biosynthesized prodigiosin to be 92.8%. PG was then absorbed by P(NIPA)-based hydrogels at temperatures between 28-48°C. This is a temperature range that might be encountered during the implantation of biomedical devices for localized cancer treatment via drug delivery and hyperthermia. The results obtained are shown to provide insights for the design of implantable biomedical devices for the localized treatment of breast cancer., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Prodiginine molecules (prodigiosin and obatoclax) are well-known pH-chromic dyes with promising anti-tumor properties. They present multiple tautomeric and rotameric forms. The protonation state and the structure of such flexible ligands in interaction with a protein are crucial to understand and to model the protein's biological activities. The determination of the protonation state via UV/vis absorption is possible if the ligand spectra of the neutral and protonated states are sufficiently different, and also if we can eliminate other factors potentially impacting the spectrum. Upon measuring the absorption spectra of the ligand in solution, varying solvents and pH values, we have determined that the optical properties of prodigiosin and obatoclax depend on the protonation state and not on the solvent permittivity constant. In parallel, action spectroscopy (using tunable lasers coupled to ion traps) in the gas phase of protonated and sodiated prodigiosin and obatoclax molecules has been performed to evaluate the sensitivity of the charge and the conformational state to their optical properties free of solvent. The spectra are interpreted using computational simulations of molecular structures and electronic excitations. The excitation energies are only slightly sensitive to various isomerizations, and may be used to distinguish between protonated and deprotonated states, even in the presence of a sodium counter-ion.

Anhydroexfoliamycin (1) and undecylprodigiosin (2) have been previously described as neuroprotective molecules against oxidative stress in neurons. Since oxidative stress is strongly correlated with neurodegenerative diseases, we have evaluated their effects over the principal hallmarks of Alzheimer's disease (AD). Both compounds were tested in vitro in two different neuroblastoma cellular models, one for amyloid precursor protein metabolism studies (BE(2)-M17) and another one specific for taupathology in AD (SH-SY5Y-TMHT441). Amyloid-beta (Aβ) levels, β-secretase (BACE1) activity, tau phosphorylation, extracellular signal-regulated kinase (ERK) and glycogen synthase kinase-3beta (GSK3β) expression were analyzed and while undecylprodigiosin (2) produced poor results, anhydroexfoliamycin (1) strongly inhibited GSK3β, reducing tau phosphorylation in vitro (0.1 μM). A competitive assay of anhydroexfoliamycin (1) and the specific c-Jun N-terminal kinase (JNK) inhibitor, SP600125, showed that the reduction of the phosphorylated tau levels is mediated by the JNK pathway in SH-SY5Y-TMHT441 cells. Thus, this compound was tested in vivo by intraperitoneal administration in 3xTg-AD mice, confirming the positive results registered in the in vitro assays. This work presents anhydroexfoliamycin (1) as a promising candidate for further studies in drug development against neurodegenerative diseases., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)