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PubMed2005

Influence of fusaric acid on phenazine-1-carboxamide synthesis and gene expression of Pseudomonas chlororaphis strain PCL1391.

Production of the antifungal metabolite phenazine-1-carboxamide (PCN) by Pseudomonas chlororaphis strain PCL1391 is essential for the suppression of tomato foot and root rot caused by the soil-borne fungus F. oxysporum f. sp. radicis-lycopersici. The authors have shown previously that fusaric acid (FA), a phytotoxin produced by Fusarium oxysporum, represses the production of PCN and of the quorum-sensing signal N-hexanoyl-l-homoserine lactone (C(6)-HSL). Here they report that PCN repression by FA is maintained even during PCN-stimulating environmental conditions such as additional phenylalanine, additional ferric iron and a low Mg(2+) concentration. Constitutive expression of phzI or phzR increases the production of C(6)-HSL and abolishes the repression of PCN production by FA. Transcriptome analysis using P. chlororaphis PCL1391 microarrays showed that FA represses expression of the phenazine biosynthetic operon (phzABCDEFGH) and of the quorum-sensing regulatory genes phzI and phzR. FA does not alter expression of the PCN regulators gacS, rpoS and psrA. In conclusion, reduction of PCN levels by FA is due to direct or indirect repression of phzR and phzI. Microarray analyses identified genes of which the expression is strongly influenced by FA. Genes highly upregulated by FA are also upregulated by iron starvation in Pseudomonas aeruginosa. This remarkable overlap in the expression profile suggests an overlapping stress response to FA and iron starvation.

Fusaric Acid↗
PubMed2006

Regulatory roles of psrA and rpoS in phenazine-1-carboxamide synthesis by Pseudomonas chlororaphis PCL1391.

Production of the secondary metabolite phenazine-1-carboxamide (PCN) by Pseudomonas chlororaphis PCL1391 is crucial for biocontrol activity against the phytopathogen Fusarium oxysporum f. sp. radicis lycopersici on tomato. Regulation of PCN production involves the two-component signalling system GacS/GacA, the quorum-sensing system PhzI/PhzR and the regulator PsrA. This paper reports that a functional rpoS is required for optimal PCN and N-hexanoyl-L-homoserine lactone (C(6)-HSL) production. Constitutive expression of rpoS is able to complement partially the defect of a psrA mutant for PCN and N-acylhomoserine lactone production. Western blotting shows that rpoS is regulated by gacS. Altogether, these results suggest the existence of a cascade consisting of gacS/gacA upstream of psrA and rpoS, which influence expression of phzI/phzR. Overproduction of phzR complements the effects on PCN and C(6)-HSL production of all mutations tested in the regulatory cascade, which shows that a functional quorum-sensing system is essential and sufficient for PCN synthesis. In addition, the relative amounts of PCN, phenazine-1-carboxylic acid and C(6)-HSL produced by rpoS and psrA mutants harbouring a constitutively expressed phzR indicate an even more complex network of interactions, probably involving other genes. Preliminary microarray analyses of the transcriptomics of the rpoS and psrA mutants support the model of regulation described in this study and allow identification of new genes that might be involved in secondary metabolism.

4-Butyrolactone↗
PubMed1988

Structure of the pseudomonad fungal antibiotic phenazine-1-carboxylic acid.

C13H8N2O2, Mr = 224.2, monoclinic, Cc, a = 3.955 (1), b = 19.278 (4), c = 13.468 (1) A, beta = 98.90 (2) degrees, V = 1015 (2) A3, Z = 4, D chi = 1.468 Mg m-3, lambda (Mo K alpha) = 0.7107 A, mu = 0.061 mm-1, F(000) = 464, T = 293 (2) K, R = 0.047 for 571 observed reflections. The crystal-structure determination of the title compound, a phenazine antibiotic from Pseudomonas fluorescens 2-79 (NRRL B-15132), confirms its structure as phenazine-1-carboxylic acid. The molecular packing is described by discrete stacks of molecules parallel to the a axis with the distance between the essentially planar molecules being ca 3.96 A; there are no significant intermolecular contacts in the lattice.

Anti-Bacterial Agents↗
PubMed1996

Induction of phenazine biosynthesis in cultures of Pseudomonas aeruginosa by L-N-(3-oxohexanoyl)homoserine lactone.

A range of Pseudomonas spp. and other Gram-negative bacteria were screened for induction of antimicrobial activity in response to the autoregulatory factor L-N-(3-oxohexanoyl)homoserine lactone. In one of these, P. aeruginosa ATCC 10145, the production of phenazine metabolites was shown to be inducible in a dose-dependent manner. The production of phenazine-1-carboxamide increased over 50-fold compared to control cultures when supplemented with 200 micrograms/ml of the autoregulator. In addition, the production of an unidentified polar antibacterial substance by this strain increased with autoregulator concentration.

4-Butyrolactone↗
PubMed1987

Prooxidative activities of 10 phenazine derivatives relative to that of clofazimine.

The objective of this study was to investigate the relationship between the antimycobacterial properties of the antileprosy drug clofazimine and its stimulatory effect on the release of reactive oxidants by polymorphonuclear leukocytes by using a variety of phenazine derivatives. The effects of these compounds on myeloperoxidase-mediated iodination, luminol-enhanced chemiluminescence, and the release of superoxide anion by polymorphonuclear leukocytes were investigated. Dissociation of the antimycobacterial and prooxidative effects of clofazimine was possible by manipulation of the chemical group in position 2 of the phenazine molecule. When nitrogen-containing substituents in this position were replaced by oxygen, the mode of the prooxidative action of the compounds was altered.

Clofazimine↗
PubMed1989

Structure-activity relationships of tetramethylpiperidine-substituted phenazines against Mycobacterium leprae in vitro.

In a previous study of structure-activity relationships of selected phenazines against Mycobacterium leprae in vitro, compounds containing a 2,2,6,6-tetramethylpiperidine substitution at the imino nitrogen were most active. Therefore, the effect of substitution at the para positions of the phenyl and anilino groups in tetramethylpiperidine-substituted phenazines was assessed. As determined by radiorespirometry, activity in ascending order was observed in compounds substituted with hydrogens or fluorines, ethoxy groups, methyl groups, chlorines, and bromines and correlated with partition coefficients in octanol-water.

Anti-Bacterial Agents↗
PubMed2006

Pip, a novel activator of phenazine biosynthesis in Pseudomonas chlororaphis PCL1391.

Secondary metabolites are important factors for interactions between bacteria and other organisms. Pseudomonas chlororaphis PCL1391 produces the antifungal secondary metabolite phenazine-1-carboxamide (PCN) that inhibits growth of Fusarium oxysporum f. sp. radius lycopersici the causative agent of tomato foot and root rot. Our previous work unraveled a cascade of genes regulating the PCN biosynthesis operon, phzABCDEFGH. Via a genetic screen, we identify in this study a novel TetR/AcrR regulator, named Pip (phenazine inducing protein), which is essential for PCN biosynthesis. A combination of a phenotypical characterization of a pip mutant, in trans complementation assays of various mutant strains, and electrophoretic mobility shift assays identified Pip as the fifth DNA-binding protein so far involved in regulation of PCN biosynthesis. In this regulatory pathway, Pip is positioned downstream of PsrA (Pseudomonas sigma factor regulator) and the stationary-phase sigma factor RpoS, while it is upstream of the quorum-sensing system PhzI/PhzR. These findings provide further evidence that the path leading to the expression of secondary metabolism gene clusters in Pseudomonas species is highly complex.

Amino Acid Sequence↗
PubMed1970

Regulation of aromatic amino acid biosynthesis in phenazine-producing strains of Pseudomonas.

Regulation of 3-deoxy-d-arabino-heptulosonate-7-phosphate (DAHP) synthetase was studied in eight strains of Pseudomonas which synthesize phenazine compounds. Repression studies with individual aromatic amino acids led to the finding that enzyme synthesis was repressed in only one strain, P. aureofaciens B1543p, and by only one amino acid, l-tyrosine. Feedback inhibition by the aromatic amino acids varied from strain to strain in terms of the type of inhibitory control, and the particular acid or acids which inhibited. Prephenate and chorismate, as well as a number of naturally occurring phenazine compounds, inhibited the DAHP synthetase activity to varying degrees.

Amino Acids↗
PubMed1984

Effect of ammonia, darkness, and phenazine methosulfate on whole-cell nitrogenase activity and Fe protein modification in Rhodospirillum rubrum.

A procedure for the immunoprecipitation of Fe protein from cell extracts was developed and used to monitor the modification of Fe protein in vivo. The subunit pattern of the isolated Fe protein after sodium dodecyl sulfate-polyacrylamide gel electrophoresis was assayed by Coomassie brilliant blue protein staining and autoradiographic 32P detection of the modifying group. Whole-cell nitrogenase activity was also monitored during Fe protein modification. The addition of ammonia, darkness, oxygen, carbonyl cyanide m-chlorophenylhydrazone, and phenazine methosulfate each resulted in a loss of whole-cell nitrogenase activity and the in vivo modification of Fe protein. For ammonia and darkness, the rate of loss of nitrogenase activity was similar to that for Fe protein modification. The reillumination of a culture incubated in the dark brought about a rapid recovery of nitrogenase activity and the demodification of Fe protein. Cyclic dark-light treatments resulted in matching cycles of nitrogenase activity and Fe protein modification. Carbonyl cyanide m-chlorophenylhydrazone and phenazine methosulfate treatments caused an immediate loss of nitrogenase activity, whereas Fe protein modification occurred at a slower rate. Oxygen treatment resulted in a rapid loss of activity but only an incomplete modification of the Fe protein.

Adenosine Triphosphate↗
PubMed1998

A seven-gene locus for synthesis of phenazine-1-carboxylic acid by Pseudomonas fluorescens 2-79.

Pseudomonas fluorescens 2-79 produces the broad-spectrum antibiotic phenazine-1-carboxylic acid (PCA), which is active against a variety of fungal root pathogens. In this study, seven genes designated phzABCDEFG that are sufficient for synthesis of PCA were localized within a 6.8-kb BglII-XbaI fragment from the phenazine biosynthesis locus of strain 2-79. Polypeptides corresponding to all phz genes were identified by analysis of recombinant plasmids in a T7 promoter/polymerase expression system. Products of the phzC, phzD, and phzE genes have similarities to enzymes of shikimic acid and chorismic acid metabolism and, together with PhzF, are absolutely necessary for PCA production. PhzG is similar to pyridoxamine-5'-phosphate oxidases and probably is a source of cofactor for the PCA-synthesizing enzyme(s). Products of the phzA and phzB genes are highly homologous to each other and may be involved in stabilization of a putative PCA-synthesizing multienzyme complex. Two new genes, phzX and phzY, that are homologous to phzA and phzB, respectively, were cloned and sequenced from P. aureofaciens 30-84, which produces PCA, 2-hydroxyphenazine-1-carboxylic acid, and 2-hydroxyphenazine. Based on functional analysis of the phz genes from strains 2-79 and 30-84, we postulate that different species of fluorescent pseudomonads have similar genetic systems that confer the ability to synthesize PCA.

Amino Acid Sequence↗
PubMed2003

Phenazine-1-carboxylic acid, a secondary metabolite of Pseudomonas aeruginosa, alters expression of immunomodulatory proteins by human airway epithelial cells.

Pseudomonas aeruginosa is a gram-negative bacterium that causes both acute and chronic lung disease in susceptible patient populations. P. aeruginosa secretes numerous proteins and secondary metabolites, many of which have biological effects that likely contribute to disease pathogenesis. An unidentified small-molecular-weight factor was previously reported to increase IL-8 release both in vitro and in vivo. To identify this factor, we subjected the <3-kDa fraction from P. aeruginosa-conditioned medium to HPLC analysis. A peak fraction that stimulated IL-8 release was found by mass spectrometry to have a molecular mass (MM) of 224 Da. On the basis of this MM and other biochemical properties, we hypothesized that the factor was phenazine-1-carboxylic acid (PCA). Subsequent studies and comparison with purified PCA confirmed this hypothesis. Purified PCA exhibited a number of biological effects in human airway epithelial cells, including increasing IL-8 release and ICAM-1 expression, as well as decreasing RANTES and monocyte chemoattractant protein-1 (MCP-1) release. PCA also increased intracellular oxidant formation as measured by electron paramagnetic resonance and by an intracellular oxidant-sensitive probe. Antioxidants inhibited PCA-dependent increases in IL-8 and ICAM-1, suggesting that oxidants contributed to these effects. However, in contrast to the related phenazine compound pyocyanin, PCA did not oxidize NAD(P)H at physiologically relevant pH, providing preliminary evidence that PCA and pyocyanin may have distinct redox chemistries within the cell. Thus PCA is a biologically active factor secreted by P. aeruginosa that has several activities that could alter the host immune and inflammatory response and thereby contribute to bacterial disease pathogenesis.

Adjuvants, Immunologic↗
PubMedDate not supplied

[Interaction of DNA with phenazine series compounds].

Complexes of DNA with phenazine compounds: neutral red, phenosaphranine; and 3-amino-7-dimethylamino-2-methyl-5-phenylphenazine were studied by viscosimetry and the dynamic birefringence technique. It is shown that, when complexing with DNA, each of the ligands induces specific changes in its macromolecular structure. Models of the binding of the compounds to DNA are proposed. It is shown that, depending on the location of bulk substituents of the phenazine chromophore, several variants of intercalation binding are realized, which differ by the orientation of the chromophore in the intercalation site.

Animals↗
PubMedDate not supplied

[The production of phenazine antibiotics by the Pseudomonas aureofaciens strain with plasmid-controlled resistance to cobalt and nickel].

Plasmid pBS501 responsible for the resistance of the wild-type Pseudomonas sp. BS501 (pBS501) to cobalt and nickel ions was conjugatively transferred to the rhizosphere Pseudomonas aureofaciens strain BS1393, which is able to synthesize phenazine antibiotics and to suppress a wide range of phytopathogenic microorganisms. The transconjugant P. aureofaciens BS1393 (pBS501) turned out to be resistant to cobalt and nickel with an MIC of 8 mM. When grown in a synthetic medium with 0.25 mM cobalt, the transconjugant accumulated 6 times more cobalt than the wild-type strain BS501 (pBS501) (1.2 and 0.2 microgram Co/mg protein). Electron microscopic studies showed that cobalt accumulates on the surface of transconjugant cells in the form of electron-opaque granules. In a culture medium with 2 mM cobalt or nickel, strain BS1393 produced phenazine-1-carboxylic acid in trace amounts. The transconjugant P. aureofaciens BS1393 (pBS501) produced this antibiotic in still smaller amounts. Unlike the parent strain BS1393, the transconjugant P. aureofaciens BS1393 (pBS501) was able to suppress in vitro the growth of the phytopathogenic fungus Gaeumannomyces graminis var. tritici 1818 in a medium containing 0.5 mM cobalt or nickel.

Anti-Bacterial Agents↗
PubMed1987

Studies on the mechanism of T cell inhibition by the Pseudomonas aeruginosa phenazine pigment pyocyanine.

Pseudomonas aeruginosa and its products have been shown to inhibit mitogen-induced human lymphocyte blastogenesis as measured by [3H]TdR uptake. The phenazine pigment pyocyanine has been identified as one of the inhibitors present in cellfree culture supernatants. To determine the mechanism of the inhibitory action of pyocyanine, we studied its effect on the early stages of T cell activation. Pyocyanine inhibited lymphocyte stimulation induced by specific antigens, the lectin concanavalin A and the calcium ionophore, ionomycin, suggesting that its inhibitory effect is not dependent on interference with the T cell antigen receptor complex itself. Using quin-2, we showed that pyocyanine did not interfere with the mitogen-induced increase in cytosolic-free Ca2+. We also showed that pyocyanine did not interfere with the function of calmodulin stimulated Ca2+-Mg2+ ATPase activity, indicating that the mechanism of action of pyocyanine differs from that of the structurally related phenothiazine compounds. Analysis of IL 2 production and IL 2 receptor expression clearly showed that pyocyanine inhibits the production of this essential lymphokine as well as the expression of IL 2 receptors on the T cell membrane. This inhibition is dose dependent and not due to cellular toxicity. There was parallel inhibition of growth in cell volume as well as [3H]TdR uptake. Thus, our results demonstrate that pyocyanine inhibits T cell proliferation by decreasing the production of the critical lymphokine IL 2 and by decreasing the expression of the IL 2 receptor. Local suppression of lymphocyte stimulation by phenazine pigments such as pyocyanine may interfere with cellular immune responses that may be necessary for eradication of chronic infection with P. aeruginosa.

Adult↗
PubMed1993

Activity of phenazine analogs against Mycobacterium leprae infections in mice.

Twenty-five compounds structurally related to clofazimine were tested for their ability to inhibit the growth of Mycobacterium leprae using the kinetic method of drug evaluation in the mouse foot pad model of leprosy. Seven of the phenazine derivatives displayed anti-M. leprae activity comparable to that of clofazimine when administered at a concentration of 0.01% (w/w) in the diet. Three of the compounds, B746, B4087, and B4101, were active when administered at 0.001% in the diet. At a dietary concentration of 0.0001%, B4087 and B4101 were slightly more active than clofazimine, while B746 was less active. In the kinetic method of drug evaluation, greater anti-M. leprae activity of phenazine derivatives was generally associated with greater pigmentation of abdominal fat. Of the compounds which did not cause pigmentation when fed at a concentration of 0.01% in the diet B4090 was the most active. This compound also inhibits the growth of a clofazimine-resistant M. smegmatis strain.

Abdomen↗
PubMed2004

Structural changes upon reduction of dipyrido[2,3-a:3',2'-c]phenazine probed by vibrational spectroscopy, ab initio calculations, and deuteration studies.

A series of bridging ligands, dipyrido[2,3-a:3',2'-c]phenazine (ppb), dipyrido[2,3-a:3',2'-c]-6,7-dichlorophenazine (ppbCl2), and dipyrido[2,3-a:3',2'-c]-6,7-dimethylphenazine (ppbMe2), and their binuclear copper(I) complexes have been synthesized, and their spectral properties were measured. The single-crystal structure of the complex, [(PPh3)2Cu(mu-ppbCl2)Cu(PPh3)2](BF4)2 in the monoclinic space group P21/c, 18.2590(1), 21.1833(3), 23.2960(3) A with Z = 4 is reported. The copper(I) complexes are deeply colored through MLCT transitions in the visible region. The vibrational spectra of the ligands have been modeled using ab initio hybrid density functional theory (DFT) methods (B3LYP/6-31G(d)) and compared to experimental FT-Raman and IR data. The DFT calculations are used to interpret the resonance Raman spectra, and thus the electronic spectra, of the complexes. The preferential enhancement of modes associated with the phenanthroline section of the ligands with blue excitation (lambda(exc) = 457.9 nm) over phenazine-based modes with redder excitation (lambda(exc) = 514.5 and 632.8 nm) suggests the 2 MLCT transitions terminated on different unoccupied MOs are present under the visible absorption envelope. The radical anion species of the ligands are prepared by the electrochemical reduction of the binuclear copper(I) complexes; no evidence of dechelation prevalent in other copper(I) complexes is observed. The resonance Raman spectra of the reduced complexes are dramatically different from those of the parent species. Across the series common bands are observed at about 1590 and 1570 cm(-1) which do not shift with reduction but are altered in intensity. The normal-mode analysis of the radical anion species suggests that these normal modes primarily involve bond length distortions that are unaffected by reduction.

Journal Article↗
PubMed2004

Metal vs ligand reduction in complexes of dipyrido[3,2-a:2',3'-c]phenazine and related ligands with [(C5Me5)ClM]+ (M = Rh or Ir): evidence for potential rather than orbital control in the reductive cleavage of the metal-chloride bond.

Complexes between the chlorometal(III) cations [(C5Me5)ClM]+, M = Rh or Ir, and the 1,10-phenanthroline-derived alpha-diimine (N--N) ligands dipyrido[3,2-a:2',3'-c]phenazine (dppz), 1,4,7,10-tetraazaphenanthrene (tap), or 1,10-phenanthroline-5,6-dione (pdo) were investigated by cyclic voltammetry, EPR, and UV-vis-NIR spectroelectrochemistry with respect to either ligand-based or metal-centered (and then chloride-dissociative) reduction. Two low-lying unoccupied molecular orbitals (MOs) are present in each of these three N wedge N ligands; however, their different energies and interface properties are responsible for different results. Metal-centered chloride-releasing reduction was observed for complexes of the DNA-intercalation ligands dppz and tap to yield compounds [(N--N)(C5Me5)M] in a two-electron step. The separation of alpha-diimine centered optical orbitals and phenazine-based redox orbitals is apparent from the EPR and UV-vis-NIR spectroelectrochemistry of [(dppz)(C5Me5)M](0/*-/2-). In contrast, the pdo complexes undergo a reversible one-electron reduction to yield o-semiquinone radical complexes [(pdo)(C5Me5)ClM]* before releasing the chloride after the second electron uptake. The fact that the dppz complexes undergo a Cl(-)-dissociative two-electron reduction despite the presence of a lowest lying pi* MO (b1(phz)) with very little overlap to the metal suggests that an unoccupied metal/chloride-based orbital is lower in energy. This assertion is confirmed both by the half-wave reduction potentials of the ligands (tap, -1.95 V; dppz, -1.60 V; pdo, -0.85 V) and by the typical reduction peak potentials of the complexes [(L)(C5Me5)ClM](PF6) (tap, -1.1 V; dppz, -1.3 V; pdo, -0.6 V; all values against Fc(+/0)).

Journal Article↗
PubMed1998

Neutral Guest Capture via Lewis Acid/Base Molecular Square Receptors. X-ray Crystal Structure of {Cyclobis[(cis-(dppp)Pt(4-ethynylpyridyl)(2))(cis- (PEt(3))(2)Pt)]Ag(2)}(+6)(phenazine)- ((-)OSO(2)CF(3))(6).

Interaction of {cyclobis[(cis-(dppp)Pt(4-ethynylpyridyl)(2))(cis-(L)M)]Ag(2)}(+6)((-)OSO(2)CF(3))(6), where M = Pt(II) or Pd(II) and L = dppp or 2PEt(3), with pyridine, pyrazine, phenazine, or 4,4'-dipyridyl ketone results in coordination Lewis acid/base host-guest assemblies via the "pi-tweezer effect" and mono or bis neutral guest coordination. All host-guest complexes are air stable microcrystalline solids with decomposition points greater than 170 degrees C. The homometallic Pt(II) receptors are more stable than the heteroaromatic Pt(II)-Pd(II) receptors toward heteratom-containing aromatic guests. The X-ray crystal structure of the host-guest complex {cyclobis[(cis-(dppp)Pt(4-ethynylpyridyl)(2))(cis-(PEt(3))(2)Pt)]Ag(2)}(+6)(phenazine)((-)OSO(2)CF(3))(6) is reported. The crystals with the empirical formula C(62)H(68)AgF(9)N(3)O(9)P(4)Pt(2)S(3) are triclinic P&onemacr; with a = 12.3919(8) Å, b = 17.160(1) Å, c = 18.932(1) Å, alpha = 90.892(1) degrees, beta = 97.127(1) degrees, gamma = 89.969(1) degrees, and Z = 2.

Journal Article↗