The Prodiginine family consists of primarily red-pigmented tripyrrole secondary metabolites that were first characterized in the Gram-negative bacterial species
and demonstrates a wide array of ...biological activities and applications. Derivatives of prodiginine have since been characterized in the marine γ-proteobacterium,
. Although biosynthetic gene clusters involved in prodiginine synthesis display homology among genera, there is an evident structural difference in the resulting metabolites. This review will summarize prodiginine biosynthesis, bioactivity, and gene regulation in
in comparison to the previously characterized species of
, discuss the ecological contributions of
in the marine microbiome and their eukaryotic hosts, and consider the importance of modern functional genomics and classic DNA manipulation to understand the overall prodiginine biosynthesis pathway.
Bacterial metabolites represent an invaluable source of bioactive molecules which can be used as such or serve as chemical frameworks for developing new antimicrobial compounds for various ...applications including crop protection against pathogens. Prodiginines are tripyrrolic, red-colored compounds produced by many bacterial species. Recently, due to the use of chemical-, bio-, or mutasynthesis, a novel group of prodiginines was generated. In our study, we perform different assays to evaluate the effects of prodigiosin and five derivatives on nematodes and plant pathogenic fungi as well as on plant development. Our results showed that prodigiosin and the derivatives were active against the bacterial feeding nematode
Caenorhabditis elegans
in a concentration- and derivative-dependent manner while a direct effect on infective juveniles of the plant parasitic nematode
Heterodera schachtii
was observed for prodigiosin only. All compounds were found to be active against the plant pathogenic fungi
Phoma lingam
and
Sclerotinia sclerotiorum.
Efficacy varied depending on compound concentration and chemical structure. We observed that prodigiosin (
1
), the 12 ring-
9
, and hexenol
10
derivatives are neutral or even positive for growth of
Arabidopsis thaliana
depending on the applied compound concentration, whereas other derivatives appear to be suppressive. Our infection assays revealed that the total number of developed
H. schachtii
individuals on
A. thaliana
was decreased to 50% in the presence of compounds
1
or
9
. Furthermore, female nematodes and their associated syncytia were smaller in size. Prodiginines seem to indirectly inhibit
H. schachtii
parasitism of the plant. Further research is needed to elucidate their mode of action. Our results indicate that prodiginines are promising metabolites that have the potential to be developed into novel antinematodal and antifungal agents.
The cover feature picture shows the colorful mutasynthesis story of the production machinery for cyclic prodiginines in Pseudomonas putida KT2440. Pyrrole derivatives are supplemented to the ...fermentation broth and incorporated by a genetically modified P. putida strain. After the assembly of the highly bioactive prodiginines in P. putida, the natural product analogues are adsorbed by small polyurethane foam cubes, which can be easily fished out of the fermentation broth by the scientist. More information can be found in the full paper by J. Pietruszka et al. on page 1545 in Issue 14, 2018 (DOI: 10.1002/cbic.201800154).
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Bacterial secondary metabolites exhibit diverse remarkable bioactivities and are thus the subject of study for different applications. Recently, the individual effectiveness of tripyrrolic ...prodiginines and rhamnolipids against the plant-parasitic nematode
, which causes tremendous losses in crop plants, was described. Notably, rhamnolipid production in engineered
strains has already reached industrial implementation. However, the non-natural hydroxyl-decorated prodiginines, which are of particular interest in this study due to a previously described particularly good plant compatibility and low toxicity, are not as readily accessible. In the present study, a new effective hybrid synthetic route was established. This included the engineering of a novel
strain to provide enhanced levels of a bipyrrole precursor and an optimization of mutasynthesis, i.e., the conversion of chemically synthesized and supplemented monopyrroles to tripyrrolic compounds. Subsequent semisynthesis provided the hydroxylated prodiginine. The prodiginines caused reduced infectiousness of
for
plants resulting from impaired motility and stylet thrusting, providing the first insights on the mode of action in this context. Furthermore, the combined application with rhamnolipids was assessed for the first time and found to be more effective against nematode parasitism than the individual compounds. To obtain, for instance, 50% nematode control, it was sufficient to apply 7.8 μM hydroxylated prodiginine together with 0.7 μg/ml (~ 1.1 μM) di-rhamnolipids, which corresponded to
¼ of the individual EC
values. In summary, a hybrid synthetic route toward a hydroxylated prodiginine was established and its effects and combinatorial activity with rhamnolipids on plant-parasitic nematode
are presented, demonstrating potential application as antinematodal agents. Graphical Abstract.
Prodiginines are a large family of tripyrrole alkaloids that contain natural members produced by various bacteria and non-natural members obtained from chemical synthesis, enzymatic synthesis, and ...mutasynthesis. These compounds have attracted a great deal of attention due to their wide range of fascinating properties including anti-infective, anticancer, and immunosuppressive activities. In consideration of the great need for novel and effective anti-infective agents, this review is mainly focused on the current status of research on the anti-infective properties of prodiginines, highlighting their antibacterial, antifungal, antiprotozoal, anti-larval, and antiviral activities. Additionally, the multiple mechanisms by which prodiginines exert their anti-infective effects will also be discussed.
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CEKLJ, DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Prodiginines are a group of naturally occurring pyrrole alkaloids produced by various microorganisms and known for their broad biological activities. The production of nature‐inspired cyclic ...prodiginines was enabled by combining organic synthesis with a mutasynthesis approach based on the GRAS (generally recognized as safe) certified host strain Pseudomonas putida KT2440. The newly prepared prodiginines exerted antimicrobial effects against relevant alternative biotechnological microbial hosts whereas P. putida itself exhibited remarkable tolerance against all tested prodiginines, thus corroborating the bacterium's exceptional suitability as a mutasynthesis host for the production of these cytotoxic secondary metabolites. Moreover, the produced cyclic prodiginines proved to be autophagy modulators in human breast cancer cells. One promising cyclic prodiginine derivative stood out, being twice as potent as prodigiosin, the most prominent member of the prodiginine family, and its synthetic derivative obatoclax mesylate.
Cyclic precursors accepted: New cyclic prodigiosin derivatives were obtained by mutasynthesis in a generally recognized as safe (GRAS) certified strain of P. putida (KT2440) through a combination of organic chemistry and genetic engineering. Bioactivity studies of these prodiginines showed strong antimicrobial activity against biotechnologically relevant microorganisms as well as potent modulation of autophagy in human breast cancer cells.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Metastasis is the primary cause of death in cancer patients. Many current chemotherapeutic agents only show cytotoxic, but not antimetastatic properties. This leads to a reduction in tumor size, but ...allows cancer cells to disseminate, which ultimately causes patient death. Therefore, novel anticancer compounds with both effects need to be developed. In this work, we analyze the antimetastatic properties of prodigiosin and obatoclax (GX15-070), anticancer drugs of the Prodiginines (PGs) family. We studied PGs' effects on cellular adhesion and morphology in the human primary and metastatic melanoma cell lines, SK-MEL-28 and SK-MEL-5, and in the murine melanoma cell line, B16F10A. Cell adhesion sharply decreased in the treated cells, and this was accompanied by a reduction in filopodia protrusions and a significant decrease in the number of focal-adhesion structures. Moreover, cell migration was assessed through the wound-healing assay and cell motility was severely inhibited after 24 h of treatment. To elucidate the molecular mechanisms involved, changes in metastasis-related genes were analyzed through a gene-expression array. Key genes related to cellular invasion, migration and chemoresistance were significantly down-regulated. Finally, an in vivo model of melanoma-induced lung metastasis was established and significant differences in lung tumors were observed in the obatoclax-treated mice. Altogether, these results describe, in depth, PGs' cellular antimetastatic effects and identify in vivo antimetastatic properties of Obatoclax.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Facile, versatile, and cost-effective synthetic routes for the preparation of a range of new 3-alkyl-, 4-alkyl-, 3,4-dialkyl-, and 3-halo-4-alkyl-2,2′-bipyrrole-5-carboxaldehydes have been developed. ...These 2,2′-bipyrrole-5-carboxaldehydes offer interesting potential as building blocks for making bioactive natural and unnatural products, as demonstrated by the synthesis of B-ring functionalized prodiginines (PGs) and tambjamines.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The deeply red-colored natural compound prodigiosin is a representative of the prodiginine alkaloid family, which possesses bioactivities as antimicrobial, antitumor, and antimalarial agents. Various ...bacteria including the opportunistic human pathogen Serratia marcescens and different members of the Streptomycetaceae and Pseudoalteromonadaceae produce prodiginines. In addition, these microbes generally accumulate many structurally related alkaloids making efficient prodiginine synthesis and purification difficult and expensive. Furthermore, it is known that structurally different natural prodiginine variants display differential bioactivities. In the herein described mutasynthesis approach, 13 different derivatives of prodigiosin were obtained utilizing the GRAS (generally recognized as safe) classified strain Pseudomonas putida KT2440. Genetic engineering of the prodigiosin pathway together with incorporation of synthetic intermediates thus resulted in the formation of a so far unprecedented structural diversity of new prodiginine derivatives in P. putida. Furthermore, the formed products allow reliable conclusions regarding the substrate specificity of PigC, the final condensing enzyme in the prodigiosin biosynthesis pathway of S. marcescens. The biological activity of prodigiosin toward modulation of autophagy was preserved in prodiginine derivatives. One prodiginine derivative displayed more potent autophagy inhibitory activity than the parent compound or the synthetic clinical candidate obatoclax.
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IJS, KILJ, NUK, PNG, UL, UM
Apoptosis is involved in the action of several (and perhaps all) cancer-chemotherapeutic agents. Prodiginines are a family of natural red pigmented secondary metabolites, produced by different ...bacteria and most of them are characterized by a common pyrrolylpyrromethene skeleton. The biosynthesis of prodigiosin and derivatives has been extensively studied in Serratia marcescens. S. marcescens is a Gramnegative bacterium belonging to Enterobacteriaceae. Prodiginines show numerous biological activities pointing out immunosuppressive and anticancer properties. Some prodiginines displayed apoptotic effects in vitro and antitumor activity in vivo. Their cytotoxic effect is attributed to the presence of the C- 6 methoxy substituent. The A-pyrrole ring plays a key role in both the copper nuclease activity and the cytotoxicity of prodiginines. Here we review the main characteristics of prodigiosin and their derivatives as well as the most prominent pharmacological activity of prodiginines and related compounds, including novel synthetic PG-derivatives with lower toxicity like GX15-070 (Obatoclax). The molecular targets of prodiginines are discussed and the mechanism of action for these molecules is a current topic in biomedicine with a real therapeutica potential in the clinic.
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