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PubMed2003

Zinc and copper complexes of prodigiosin: implications for copper-mediated double-strand DNA cleavage.

[reaction: see text] Zinc(II) and copper(II) complexes of prodigiosin (1) have been characterized. All N-atoms of 1 bind Cu(II) to generate 5: the complex exhibits regiospecific oxidation of the C-pyrrole. In contrast, coordination by Zn(II) to 1 produces Zn(1)(2) (8), a 4-coordinate tetrahedral complex. The influence of these binding geometries on Cu-mediated double-strand (ds) DNA cleavage by 1 is discussed.

Anti-Bacterial Agents↗
PubMed2000

In vivo rapid reduction of alloantigen-activated CD8+ mature cytotoxic T cells by inhibitors of acidification of intracellular organelles, prodigiosin 25-C and concanamycin B.

Prodigiosin (PrG) 25-C and concanamycin B (CMB) are immunosuppressants that specifically inhibit the induction of cytotoxic T cells (CTL) without affecting the function of B cells and helper T cells in vivo. Both compounds inhibit acidification of intracellular organelles and induce destruction of cytotoxic granules and degradation of perforin in vitro. Here we show that a single intraperitoneal (i.p.) injection of PrG 25-C, and of CMB, into mice eliminates cytotoxic activity 7 days after alloantigen stimulation (when mature CTL activity has been detected in control mice), with minimal effect on the alloantigen-specific antibody titre in serum. FK506 did not suppress the cytotoxic activity with this administration schedule. Suppression was accompanied by a decrease in the CD8+ population and in perforin expression of spleen cells induced by alloantigen stimulation. The suppression of CTL activity and decrease in CD8+ cell number was detected as early as 7 hr after the injection of compounds. These results suggest that inhibitors of acidification of intracellular organelles suppress CTL activity in vivo by reducing the number of mature CD8+ CTL.

Animals↗
PubMed2003

Phosphate availability regulates biosynthesis of two antibiotics, prodigiosin and carbapenem, in Serratia via both quorum-sensing-dependent and -independent pathways.

Serratia sp. ATCC 39006 produces two secondary metabolite antibiotics, 1-carbapen-2-em-3-carboxylic acid (Car) and the red pigment, prodigiosin (Pig). We have previously reported that production of Pig and Car is controlled by N-acyl homoserine lactone (N-AHL) quorum sensing, with synthesis of N-AHLs directed by the LuxI homologue SmaI, and is also regulated by Rap, a member of the SlyA family. We now describe further characterization of the SmaI quorum-sensing system and its connection with other regulatory mechanisms. We show that the genes responsible for biosynthesis of Pig, pigA-O, are transcribed as a single polycistronic message in an N-AHL-dependent manner. The smaR gene, transcribed convergently with smaI and predicted to encode the LuxR homologue partner of SmaI, was shown to possess a negative regulatory function, which is uncommon among the LuxR-type transcriptional regulators. SmaR represses transcription of both the pig and car gene clusters in the absence of N-AHLs. Specifically, we show that SmaIR exerts its effect on car gene expression via transcriptional control of carR, encoding a pheromone-independent LuxR homologue. Transcriptional activation of the pig and car gene clusters also requires a functional Rap protein, but Rap dependency can be bypassed by secondary mutations. Transduction of these suppressor mutations into wild-type backgrounds confers a hyper-Pig phenotype. Multiple mutations cluster in a region upstream of the pigA gene, suggesting this region may represent a repressor target site. Two mutations mapped to genes encoding pstS and pstA homologues, which are parts of a high-affinity phosphate transport system (Pst) in Escherichia coli. Disruption of pstS mimicked phosphate limitation and caused concomitant hyper-production of Pig and Car, which was mediated, in part, through increased transcription of the smaI gene. The Pst and SmaIR systems define distinct, yet overlapping, regulatory circuits which form part of a complex regulatory network controlling the production of secondary metabolites in Serratia ATCC 39006.

4-Butyrolactone↗
PubMed2005

High cytotoxic sensitivity of the human small cell lung doxorubicin-resistant carcinoma (GLC4/ADR) cell line to prodigiosin through apoptosis activation.

In the present study, we describe the cytotoxicity of the new drug prodigiosin (PG) in two small cell lung carcinoma (SCLC) cell lines, GLC4 and its derived doxorubicin-resistant GLC4/ADR cell line, which overexpresses multidrug-related protein 1 (MRP-1). We observed through Western blot that PG mediated cytochrome c release, caspase cascade activation and PARP cleavage, thereby leading to apoptosis in a dose-response manner. MRP-1 expression increased after PG treatment, although that does not lead to protein accumulation. The MTT assay showed no difference in sensitivity to PG between the two cell lines. Our results support PG as a potential drug for the treatment of lung cancer as it overcomes the multidrug resistance phenotype produced by MRP-1 overexpression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

Suppression of cytotoxic T cell induction in vivo by prodigiosin 25-C.

Prodigiosin 25-C (PrG25-C) was discovered as an immunosuppressant in the course of our screening for immunomodulating substances. In this system, PrG25-C inhibited T lymphocytes proliferation and was less suppressive against B lymphocytes. PrG25-C was also a powerful inhibitor of cytotoxic T cell induction by mixed lymphocyte reaction and completely suppressed induction of H-2 specific cytotoxic cells at 12.7 nM. PrG25-C also inhibited in vivo induction of H-2 restricted cytotoxic T lymphocytes at a dose of 0.5 mg/kg but had little myelotoxicity because numbers of blood leukocytes and splenocytes of PrG25-C-treated mice were comparable to those of nonsensitized mice. No inhibitory effects of PrG25-C were observed on the production of anti-SRBC antibody. These results indicate that PrG25-C is a T-lymphocyte-specific immunosuppressant.

Animals↗
PubMed1990

A relaxed (rel) mutant of Streptomyces coelicolor A3(2) with a missing ribosomal protein lacks the ability to accumulate ppGpp, A-factor and prodigiosin.

A relaxed (rel) mutant was found among 70 thiopeptin-resistant isolates of Streptomyces coelicolor A3(2) which arose spontaneously. The ability of the rel mutant to accumulate ppGpp during Casamino acid deprivation was reduced 10-fold compared to the wild-type. Analysis of the ribosomal proteins by two-dimensional PAGE revealed that the mutant lacked a ribosomal protein, tentatively designated ST-L11. It was therefore classified as a relC mutant. The mutant was defective in producing A-factor and the pigmented antibiotic prodigiosin, in both liquid and agar cultures, but produced agarase normally. Production of actinorhodin, another pigmented antibiotic, was also abnormal; it appeared suddenly in agar cultures after 10 d incubation. Although aerial mycelium still formed, its appearance was markedly delayed. Whereas liquid cultures of the parent strain accumulated ppGpp, agar cultures accumulated only trace amounts. Instead, a substance characterized only as an unidentified HPLC peak accumulated intracellularly in the late growth phase, just before aerial mycelium formation and antibiotic production. This substance did not accumulate in mutant cells. It was found in S. lividans 66 and S. parvulus, but not in seven other Streptomyces species tested. The significance of these observations, and the relationship of the mutant to earlier rel isolates of Streptomyces is discussed.

Anthraquinones↗
PubMed2005

A GntR family transcriptional regulator (PigT) controls gluconate-mediated repression and defines a new, independent pathway for regulation of the tripyrrole antibiotic, prodigiosin, in Serratia.

Biosynthesis of the red, tripyrrole antibiotic prodigiosin (Pig) by Serratia sp. ATCC 39006 (39006) is controlled by a complex regulatory network involving an N-acyl homoserine lactone (N-AHL) quorum-sensing system, at least two separate two-component signal transduction systems and a multitude of other regulators. In this study, a new transcriptional activator, PigT, and a physiological cue (gluconate), which are involved in an independent pathway controlling Pig biosynthesis, have been characterized. PigT, a GntR homologue, activates transcription of the pigA-O biosynthetic operon in the absence of gluconate. However, addition of gluconate to the growth medium of 39006 repressed transcription of pigA-O, via a PigT-dependent mechanism, resulting in a decrease in Pig production. Finally, expression of the pigT transcript was shown to be maximal in exponential phase, preceding the onset of Pig production. This work expands our understanding of both the physiological and genetic factors that impinge on the biosynthesis of the secondary metabolite Pig in 39006.

4-Butyrolactone↗
PubMed2005

Biosynthesis of tripyrrole and beta-lactam secondary metabolites in Serratia: integration of quorum sensing with multiple new regulatory components in the control of prodigiosin and carbapenem antibiotic production.

Summary Serratia sp. ATCC 39006 (39006) uses a complex hierarchical regulatory network allowing multiple inputs to be assessed before genes involved in secondary metabolite biosynthesis are expressed. This taxonomically ill-defined Serratia sp. produces a carbapenem antibiotic (Car; a beta-lactam) and a red pigmented antibiotic, prodigiosin (Pig; a tripyrrole), which are controlled by the smaIR quorum sensing (QS) locus. SmaR is a repressor of Pig and Car when levels of N-acyl- l-homoserine lactones, produced by SmaI, are low. In this study, we demonstrate direct DNA binding of purified SmaR to the promoter of the Car biosynthetic genes and abolition of this binding by the QS ligand. We have also identified multiple new secondary metabolite regulators. QS controls production of secondary metabolites, at least in part, by modulating transcription of three genes encoding regulatory proteins, including a putative response regulator of the GacAS two-component signalling system family, a novel putative adenylate cyclase and Rap (regulator of antibiotic and pigment). Mutations in another gene encoding a novel predicted global regulator, pigP, are highly pleiotropic; PigP has a significant "master" regulatory role in 39006 where it controls the transcription of six other regulators. The PigP protein and its homologues define a new family of regulators and are predicted to bind DNA via a helix-turn-helix domain. There are regulatory overlaps between the QS and PigP regulons that enable the information from different physiological cues to be funnelled into the control of secondary metabolite production.

Amino Acid Sequence↗
PubMed2002

Prodigiosin induces caspase-9 and caspase-8 activation and cytochrome C release in Jurkat T cells.

Prodigiosin (PG) is an active component of bacterial origin, with reported apoptotic effects. We examined the activation of caspases-9, -8, and -3 in PG-treated Jurkat cells in a dose-response study. These caspases were activated in apoptotic cells, as judged by the appearance of cleavage products from procaspases, and cytochrome c (cyt c) was released to the cytosol. In addition, PG induced the cleavage of poly (ADP-ribose) polymerase (PARP). This study demonstrates that the activation of caspases-9, -8, and -3 mediates PG-induced apoptosis.

Anti-Bacterial Agents↗
PubMed1972

Separation of prodigiosenes and identification as prodigiosin syntrophic pigment from mutant pairs of Serratia marcescens.

Countercurrent distribution is capable of resolving mixtures of closely related prodigiosene pigments. Syntrophic pigment produced by several pairs of Serratia marcescens color mutants was identified as prodigiosin (2-methyl-3-amyl-6-methoxyprodigiosene) by countercurrent distribution, soda lime pyrolysis, and other techniques. The metabolic block of mutant strain H-462, derived from parent strain HY, was located between the blocks of mutant strains OF and WF, both derived from parent strain Nima.

Bacteriological Techniques↗
PubMed2003

Prodigiosin induces apoptosis by acting on mitochondria in human lung cancer cells.

Prodigiosin (PG) is a secondary metabolite, isolated from a culture of Serratia marcescens, which has shown potent cytotoxicity against various human cancer cell lines as well as immunosuppressive activity. The purpose of this study was to evaluate the role of mitochondria in PG-induced apoptosis. Therefore, we evaluated the apoptotic action of PG in GLC4 small cell lung cancer cell line by Hoechst 33342 staining. In these cells, we examined mitochondrial apoptosis-inducing factor (AIF) and cytochrome c (cyt c) release to the cytosol in PG time-response studies. These findings suggest that PG induces apoptosis in both caspase-dependent and caspase-independent pathways.

Apoptosis↗
PubMed1995

Prodigiosin 25-C suppression of cytotoxic T cells in vitro and in vivo similar to that of concanamycin B, a specific inhibitor of vacuolar type H(+)-ATPase.

The effects of prodigiosin 25-C (PrG) which preferentially suppresses cytotoxic T cells (CTL), was examined in comparison with concanamycin B (CMB), a specific inhibitor of vacuolar type H(+)-ATPase (V-ATPase). PrG and CMB directly inhibited the cytotoxic function of CTL and neutralized acidic organelles of CTL in vitro. In addition, PrG or CMB was injected in C57BL/6 mice after immunization with an allogeneic mastocytoma, P815. PrG and CMB inhibited the killing activity of CTL against the tumor and reduced the population of CD8+ cells without affecting CD4+ and B220+ populations in the spleen. PrG and CMB had only a negligible effect on antibody production induced by sheep red blood cells (SRBC) and mitogenic responses of lymphocytes. These results suggest that PrG and CMB have similar immunosuppressive properties at least through their inhibitory effects on acidification of intracellular organelles required for the effective function of CTL.

Adenosine Triphosphatases↗
PubMed2003

Effects of the proapoptotic drug prodigiosin on cell cycle-related proteins in Jurkat T cells.

Prodigiosin (PG) is a red pigment produced by Serratia marcescens with immunosuppressive and apoptotic activities. In this study, we sought to examine the effect of PG on cell cycle-related proteins. The antiproliferative activity of PG was tested using human Jurkat leukaemia T cells in culture. PG-inhibited cell proliferation was determined using thymidine incorporation assay. PG-arrested cell cycle was analysed using immunoblot analysis with specific antibodies against cell cycle-related proteins and kinase assays of cdk2. Apoptosis was determined by Hoechst staining and analysis of DNA fragmentation. PG inhibited cyclin E, cdk2, p27 and p21, the induction of the cyclin A-cdk2 and cyclin E-cdk2 kinase activity, and the phosphorylation of Rb in leukaemic Jurkat cells. We confirmed that PG induces apoptosis by the characteristic DNA laddering pattern and condensed nuclei or apoptotic bodies identified by fluorescence microscopy. These results indicate that PG and other family members form a new group of molecules with a common mechanism of action and specific molecular targets, raising the possibility of their therapeutic use as antineoplastic drugs.

Apoptosis↗
PubMed2001

Prodigiosin blocks T cell activation by inhibiting interleukin-2Ralpha expression and delays progression of autoimmune diabetes and collagen-induced arthritis.

Prodigiosin (PDG) was previously reported to be a T cell-specific immunosuppressant. Here we describe the mechanism of action of PDG in T cells and the effect of PDG on autoimmune diseases. PDG selectively suppresses concanavalin A (Con A)-induced T cell proliferation, but has little effect on lipopolysaccharide-induced proliferation of B cells and nitric oxide production of macrophages. Although PDG does not block interleukin (IL)-2 production, it efficiently inhibits interleukin-2 receptor alpha-chain (IL-2Ralpha) expression, and this results in a disruption of the IL-2/IL-2R signaling pathway, on which a great part of the regulation of T cell activation depends. PDG blocks T cell differentiation into effector helper T cells secreting interferon-gamma and IL-4 as well as into effector cytotoxic T lymphocytes expressing perforin, which is at least in part resulting from inhibition of the IL-2/IL-2R signaling. PDG indirectly blocks signal transducer and activator of transcription activation by inhibiting cytokine signalings in Con A-activated T cells, although it does not inhibit the activation of nuclear factor-kappaB, nuclear factor of activated T cells, and activator protein-1. As direct evidence of immunosuppression in vivo, we show that PDG markedly reduced blood glucose levels and cellular infiltration into the pancreatic islets in nonobese diabetic mice, and that it also delays the onset of collagen-induced arthritis in DBA/1 mice. In conclusion, our results demonstrate that PDG has a unique mode of action, namely, that it blocks T cell activation by inhibiting primarily IL-2Ralpha expression in the IL-2/IL-2R signaling, and show that this compound represents a promising immunosuppressant candidate for the treatment of autoimmune diseases.

Animals↗
PubMed2002

Heptyl prodigiosin, a bacterial metabolite, is antimalarial in vivo and non-mutagenic in vitro.

Heptyl prodigiosin was purified from a culture of alpha-proteobacteria isolated from a marine tunicate collected in Zamboanga, Philippines, as part of a program to screen natural products for antiparasitic activity. An in vitro antimalarial activity similar to that of quinine was found against the chloroquine-sensitive strain Plasmodium falciparum 3D7. The in vitro antimalarial activity was about 20 times the in vitro cytotoxic activity against L5178Y mouse lymphocytes. A single subcutaneous administration of 5 and 20 mg/kg significantly extended survival of P. berghei ANKA strain-infected mice but also caused sclerotic lesions at the site of injection. A single administration by gavage of 50 mg/kg did not increase survival time. The compound was not found to be mutagenic using in vitro micromethods for the Ames Salmonella typhimurium assay and the micronucleus assay using L5178Y mouse lymphoma cells.

Alphaproteobacteria↗
PubMedDate not supplied

[Correlation between the synthesis of extracellular proteases and the synthesis of the red pigment prodigiosin in Serratia marcescens].

A correlation has been established between synthesis of exocellular protease and synthesis of a red pigment prodigiosine by Serratia marcescens. Chloramphenicol, an inhibitor of protein synthesis, inhibits also synthesis of the pigment. Leucine, an inductor of synthesis of the exocellular protease by Serratia marcescens VI, induces also synthesis of the pigment. A mixture of 18 natural amino acids, asparagine and ammonium ions represses both synthesis of the enzyme and the pigment.

Chloramphenicol↗