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PubMed1975

Cyanide production from glycine by a homogenate from a Pseudomonas species.

A cell-free preparation with cyanide-producing activity was obtained from a bacterium, strain C, of the genus Pseudomonas. To preserve activity, an oxidizing agent, e.g., phenazine methosulphage (PMS), had to be added to the cell suspension before disruption by sonic treatment. By the procedure described, a total homogenate made from a 15% (wet weight) bacterial suspension in tris(hydroxymethyl)aminomethane-hydrochloride buffer (0.05 M, pH 8.2) and with PMS (0.4mM) exhibited about 8% of the activity obtained from a suspension of untreated bacteria. In the presence of flavine-adenine dinucleotide (0.3 mM) and PMS (0.4mM), the activity was augmented to about 16% of that of the intact cells. By gradient centrifugation the homogenate was separated into three fractions. The main enzyme activity was associated with those fractions which by electron microscopy were found to consist of membranous structures.

Buffers↗
PubMed2005

Calcium-induced virulence factors associated with the extracellular matrix of mucoid Pseudomonas aeruginosa biofilms.

Pseudomonas aeruginosa colonizes the pulmonary tissue of patients with cystic fibrosis (CF), leading to biofilm-associated infections. The pulmonary fluid of CF patients usually contains elevated concentrations of cations and may contain the P. aeruginosa redox-active pigment pyocyanin, which is known to disrupt calcium homeostasis of host cells. Since divalent cations are important bridging ions for bacterial polysaccharides and since they may play regulatory roles in bacterial gene expression, we investigated the effect of calcium ions on the extracellular matrix constituents of P. aeruginosa biofilms. For mucoid strain P. aeruginosa FRD1, calcium addition (1.0 and 10 mM as CaCl(2)) resulted in biofilms that were at least 10-fold thicker than biofilms without added calcium. Scanning confocal laser microscopy showed increased spacing between cells for the thick biofilms, and Fourier transform infrared spectroscopy revealed that the material between cells is primarily alginate. An algD transcriptional reporter demonstrated that calcium addition caused an eightfold increase in alg gene expression in FRD1 biofilms. Calcium addition also resulted in increased amounts of three extracellular proteases (AprA, LasB, and PrpL). Immunoblots of the biofilm extracellular material established that AprA was harbored within the biofilm extracellular matrix. An aprA deletion mutation and a mutation in gene for a putative P. aeruginosa calmodulin-like protein did not significantly affect calcium-induced biofilm structure. Two-dimensional gel electrophoresis showed increased amounts of phenazine biosynthetic proteins in FRD1 biofilms and in calcium-amended planktonic cultures. Spectrochemical analyses showed that the calcium addition causes a three- to fivefold increase in pyocyanin production. These results demonstrate that calcium addition affects the structure and extracellular matrix composition of mucoid P. aeruginosa biofilms, through increased expression and stability of bacterial extracellular products. The calcium-induced extracellular matrix of mucoid P. aeruginosa consists primarily of the virulence factor alginate and also harbors extracellular proteases and perhaps pyocyanin, a biomolecule that may further disrupt cellular calcium levels.

Alginates↗
PubMed2004

Degradation of acyl-homoserine lactone molecules by Acinetobacter sp. strain C1010.

A bacterium C1010, isolated from the rhizospheres of cucumbers in fields in Korea, degraded the microbial quorum-sensing molecules, hexanoyl homoserine lactone (HHSL), and octadecanoyl homoserine lactone (OHSL). Morphological characteristics and 16S rRNA sequence analysis identified C1010 as Acinetobacter sp. strain C1010. This strain was able to degrade the acyl-homoserine lactones (AHLs) produced by the biocontrol bacterium, Pseudomonas chlororaphis O6, and a phytopathogenic bacterium, Burkholderia glumae. Co-cultivation studies showed that the inactivation of AHLs by C1010 inhibited production of phenazines by P. chlororaphis O6. In virulence tests, the C1010 strain attenuated soft rot symptom caused by Erwinia carotovora ssp. carotovora. We suggest Acinetobacter sp. strain C1010 could be a useful bacterium to manipulate biological functions that are regulated by AHLs in various Gram-negative bacteria.

4-Butyrolactone↗
PubMed1998

Mechanism of pyocyanin- and 1-hydroxyphenazine-induced lung neutrophilia in sheep airways.

Pyocyanin (Pyo) and 1-hydroxyphenazine (1-HP) are extracellular products of Pseudomonas aeruginosa. To test whether these products were capable of producing an inflammatory response in the airways, combinations of Pyo and 1-HP at concentrations of 10(-4) and 10(-5) M were instilled into sheep airways, and indexes of inflammation were assessed by bronchoalveolar lavage (BAL) 24 h later. Challenge with the phenazines caused a significant dose-dependent increase in the number of cells and neutrophils recovered by BAL. Control challenges produced no such changes. The lung neutrophilia was accompanied by an increased concentration of albumin in BAL. The increases in BAL neutrophils and albumin could be blocked by treating the sheep with the 5-lipoxygenase inhibitor zileuton. Neither 1-HP nor Pyo was chemotactic to neutrophils when tested in vitro, but when alveolar macrophages (AM) were cultured in vitro in the presence of both Pyo and 1-HP (1 microM), the supernatants caused neutrophil chemotaxis. Analysis of AM culture supernatants incubated with the combination of pigments showed significant increases in leukotriene B4 and interleukin-8, and blocking these mediators separately or together reduced AM supernatant-induced neutrophil chemotaxis. We conclude that local instillation of Pyo and 1-HP can initiate an inflammatory response in the airways of sheep in vivo. This effect can be explained, in part, by the release of chemotactic factors produced by AM.

Animals↗
PubMed1967

Human liver aldehyde oxidase: differential inhibition of oxidation of charged and uncharged substrates.

HUMAN LIVER ALDEHYDE OXIDASE (ALDEHYDE: O(2) oxidoreductase, EC 1.2.3.1) has been purified 60-fold and some of its properties studied. Like aldehyde oxidase from other mammalian species, human liver aldehyde oxidase is an enzyme with dual substrate specificity, possessing the ability to catalyze not only the oxidation of aldehydes to the corresponding carboxylic acids, but also the hydroxylation of a number of nonaldehydic heterocyclic compounds; its relative activity towards the latter group of substrates is low, however, when compared with that of liver aldehyde oxidase from rabbit and guinea pig. When the aromatic aldehyde benzaldehyde is used as substrate, human liver aldehyde oxidase, like the rabbit enzyme, is strongly inhibited by menadione, estradiol-17beta, antimycin A, Triton X-100, and N-alkylphenothiazines; the human enzyme differs from the rabbit enzyme, however, in being relatively insensitive to oligomycin and Amytal. Like the rabbit enzyme, the human enzyme can catalyze the 3-hydroxylation of phenazine methosulfate (PMS) and the 6-hydroxylation of N-methylnicotinamide (NMN). With the rabbit enzyme, however, the aerobic hydroxylation of these substrates proceeds by a conventional mechanism, while with the human enzyme, the aerobic hydroxylation of PMS and NMN is anomalous in that the reaction is inhibited only by agents with affinity for the substrate-binding site, such as cyanide and N-alkylphenothiazines, and not by agents which inhibit the "internal electron transport chain" of the enzyme, such as menadione and diethylstilbestrol. This mode of oxidation appears to be unique to substrates with a positively charged quaternary nitrogen; the hydroxylation of other nonaldehydic heterocyclic substrates for the human enzyme is sensitive to conventional aldehyde oxidase inhibitors.

Amobarbital↗
PubMed1975

Effects of insulin upon fatty acids synthesis from pyruvate, lactate, and glucose in rat mammary cells.

In isolated rat mammary secretory cells, insulin stimulated fatty acid synthesis from pyruvate three times, stimulated glucose conversion to fatty acids 1.2 to 1.5 times, and decreased lactate conversion to fatty acids 20 to 30%. Incubation of glucose and pyruvate together depressed fatty acid synthesis from glucose not attributable to isotope dilution. Glucose stimulated conversion of pyruvate-2-14 carbon to fatty acids without significantly affecting pyruvate-1-14 carbon conversion to 14-carbon dioxide. At differing concentrations, the electron acceptors phenazine methosulfate and N,N,N',N'-tetramethyl-p-phenylene-diamine alleviated the depression by insulin of lactate conversion to fatty acids. The data support concepts that: (1) insulin acts at important sites other than or in addition to glucose transport in regulating mammary secretory cell metabolism and, particularly, fatty acid synthesis; (2) insulin actions upon fatty acid synthesis can vary dependent upon cellular redox state (insulin increases fatty acid synthesis in cells with a low redox state and decreases fatty acid synthesis in cells in a very reduced state); and (3) pyruvate depresses glucose carbon flux through the Embden-Meyerhof pathway.

Animals↗
PubMed1989

WS-9659 A and B, novel testosterone 5 alpha-reductase inhibitors isolated from a Streptomyces. III. Biological characteristics and pharmacological characteristics.

WS-9659 A, a novel phenazine, produced by a Streptomyces sp., had testosterone 5 alpha-reductase inhibition activity on rat, dog and human prostates. However, WS-9659 A did not show any inhibitory activities for aldose reductase on rabbit lenses and lactate dehydrogenase on pig hearts. WS-9659 A was a competitive inhibitor against testosterone 5 alpha-reductase on rat prostates by use of testosterone as a substrate. Radio receptor binding assay of androgen receptor of rat prostates revealed that WS-9659 A had no affinity for this receptor. WS-9659 A was tested subcutaneously in immature castrated rats to confirm its effect on the growth of the ventral prostates induced by testosterone propionate.

5-alpha Reductase Inhibitors↗
PubMed1993

Phenazoviridin, a novel free radical scavenger from Streptomyces sp. Taxonomy, fermentation, isolation, structure elucidation and biological properties.

Phenazoviridin is a newly discovered free radical scavenger from microorganisms. It was isolated from the culture of Streptomyces sp. HR04. The structure of phenazoviridin was determined as 6-(3-methyl-2-butenyl)phenazine-1-carboxylic acid 6-deoxy-alpha-L-talopyranose ester on the basis of its spectroscopic and physico-chemical properties. The novel substance showed strong inhibitory activity against lipid peroxidation in rat brain homogenate and exhibited antihypoxic activity in mice.

Animals↗
PubMed1997

New anticancer antibiotics pelagiomicins, produced by a new marine bacterium Pelagiobacter variabilis.

In the course of our screening for new anticancer compounds produced by marine bacteria, we found that a new genus marine bacterium Pelagiobacter variabilis produced new phenazine antibiotics, pelagiomicins A, B and C. Those compounds were labile in water and alcohols. The absolute structure of the main component, pelagiomicin A, and the structures of the minor ones were determined from the spectroscopic data and by synthesis. Pelagiomicin A exhibits activity against Gram-positive and -negative bacteria and antitumor activity in vitro and in vivo.

Antibiotics, Antineoplastic↗
PubMedDate not supplied

Search for newer antileprosy drugs.

In 1991 World Health Organization proclaimed the goal of global elimination of leprosy as a public health problem by year 2000 by implementing multidrug therapy (MDT). Since then the prevalence rate has declined by 85%. However, during the same period the incidence rate of leprosy has remained constant or even has been increasing. This suggests that it will take a long time for the eradication of leprosy and that without in-vitro cultivation of M. leprae, eradication of leprosy is not likely to be achieved. While in-vitro cultivation is a long-term goal, as an immediate measure, there is an urgent need for the development of newer drugs and newer multidrug therapy regimens. Using the in-vitro system for screening potential antileprosy drugs and also using the mouse foot-pad system we have evaluated several compounds in four classes of drugs--dihydrofolate reductase inhibitors, fluoroquinolones, rifampicin analogues and phenazines--and identified at least two compounds that appear to be more potent than dapsone, rifampicin and clofazimine. Newer combinations of rifampicin analogues and fluoroquinolones have also been identified that seem to be better than the combination of rifampicin and ofloxacin.

Animals↗
PubMed2004

Biological characterization of MLN944: a potent DNA binding agent.

MLN944 (XR5944) is a novel bis-phenazine that has demonstrated exceptional efficacy against a number of murine and human tumor models. The drug was reported originally as a dual topoisomerase I/II poison, but a precise mechanism of action for this compound remains to be determined. Several lines of evidence, including the marginal ability of MLN944 to stabilize topoisomerase-dependent cleavage, and the sustained potency of MLN944 in mammalian cells with reduced levels of both topoisomerases, suggest that other activities of the drug exist. In this study, we show that MLN944 intercalates into DNA, but has no effect on the catalytic activity of either topoisomerase I or II. MLN944 displays no significant ability to stimulate DNA scission mediated by either topoisomerase I or II compared with camptothecin or etoposide, respectively. In addition, yeast genetic models also point toward a topoisomerase-independent mechanism of action. To examine cell cycle effects, synchronized human HCT116 cells were treated with MLN944, doxorubicin, camptothecin, or a combination of the latter two to mimic a dual topoisomerase poison. MLN944 treatment was found to induce a G(1) and G(2) arrest in cells that is unlike the typical G(2)-M arrest noted with known topoisomerase poisons. Finally, transcriptional profiling analysis of xenograft tumors treated with MLN944 revealed clusters of regulated genes distinct from those observed in irinotecan hydrochloride (CPT-11)-treated tumors. Taken together, these findings suggest that the primary mechanism of action of MLN944 likely involves DNA binding and intercalation, but does not appear to involve topoisomerase inhibition.

Animals↗
PubMed2005

[Differential effect of temperature on Plt and PCA synthesis in a rsmA inactivated mutant strain of Pseudomonas sp. M-18].

Rsm (repressor of secondary metabolite) A is an mRNA binding protein which functions as a global repressor to control multiple genes at the posttranscriptional level. Using homologous recombination technique a chromosomal rsmA inactivated mutant strain M-18R was constructed in Pseudomonas sp. M-18, a strain of plant-growth-promoting rhizobacteria, which could inhibit several soilborn phytopathogens by producing secondary metabolites including phenazine-1-carboxylic acid (PCA) and pyoluteorin (Plt) in one single strain. To further study the effect of RsmA on the synthesis of Plt and PCA in the wild type strain M-18, the dynamic curves of Plt and PCA produced respectively by M-18 and M-18R were measured in KMB medium under different temperature conditions such as 37 degrees C constant, 28 degrees C constant and nonconstant (37 degrees C 4 hours at first and then 28 degrees C constant) cultivation. The synthesis of both Plt and PCA were almost inhibited in the cultures under the condition of 37 degrees C. At 28 degrees C, however, compared with the wild type strain M-18, the mutant strain produced tenfold amount of Plt, while the production of PCA decreased only about 50%. When cultivated under the nonconstant condition, the amount of Plt produced by M-18R could reach 400 microg/mL while the PCA production was not significantly affected, but in the wild type strain M-18, the amount of Plt production decreased obviously while the PCA production was not affected in comparison with the results at 28 degrees C constant. These results suggest that a temperature sensitive factor exists to function as an activator independent of RsmA to promote the synthesis of Plt in the rsmA mutant strain M-18R while it may bind with RsmA to repress the synthesis of Plt in the wild type strain M-18. But this factor did not exert any affect on the synthesis of PCA.

Bacterial Proteins↗
PubMed2006

[Negative regulation on PCA production is not correlated with positive regulation on BHL and HHL synthesis by gacA in Pseudomonas sp. M18].

At least 5 kinds of N-acyl-homoserine lactones(AHLs) were identified in Pseudomonas sp. M18. They were: N-butyryl-L-homoserine lactone(C4-HSL, BHL), N-hexanoyl-L-homoserine lactone(C6-HSL, HHL), N-(3-oxohexanoyl)-L-homoserine lactone(3-Oxo-C6-HSL, OHHL), N-(3-oxooctanoyl)-L-homoserine lactone (3-Oxo-C8-HSL, OOHL) and N-(3-oxodecanoyl)-L-homoserine lactone(3-Oxo-C10-HSL, ODHL). Compared with the wide-type strain M18, the variety of the AHLs in the gacA mutant strain M18G reduced to 4 species with the decreased quantity. But the phenazine-1-carboxylic acid (PCA) production was increased by about 2-fold. The product of rhll plays an important role in synthesizing BHL and HHL. The rhll'-'lacZ translational fusion expression plasmid pMEIZ was constructed in vector pME6015 and then was introduced into the wild-type strain M18 and the gacA mutant strain M18G. The galactosidase activity in chromosomal gacA disruption mutant was only 60% of that in the wild-type strain M18. This result suggested that GacA could regulate the rhll expression positively. There was no influence on PCA production by adding exogenous BHL and HHL and both together to the culture of strains M18 and M18G. This result suggested that there was no relation between GacA's negative regulation on PCA production and positive regulation on BHL and HHL synthesis.

4-Butyrolactone↗
PubMedDate not supplied

[Quorum-sensing regulation in soil pseudomonads].

228 strains of soil and rhizosphere pseudomonads isolated in different geographic zones were screened, with the use of two tester systems, for the capacity to produce N-acetyl-homoserine lactones (AHLs), which are autoinducers involved in quorum-sensing (QS) regulation. AHL production was found in 11.4% of the strains investigated. In five Pseudomonas chlororaphis strains shown to be active AHL producers and chosen for further study, PCR identified two QS systems that involved the phzI, phzR, csaI, and csaR genes; this finding suggests the conservative nature of these regulation systems in P. chlororaphis. Strain P. chlororaphis 449, chosen as a model object and studied in greater detail, produced three AHL species including N-butanoyl-homoserine lactone and N-hexanoyl-homoserine lactone. This strain produced three types of phenazine antibiotics, as well as siderophores and cyanide; it also exhibited antagonistic properties toward a wide spectrum of phytopathogenic fungi. The phzI and csaI genes, coding for synthases of AHLs of two types, were cloned and sequenced; mutants with knocked-out phzI and csal genes were obtained. With the use of transposon mutagenesis and the gene substitution method, mutations were obtained in the global expression regulator genes gacS, coding for the GacA-GacS regulation system kinase, and rpoS, coding for the sigma S subunit of RNA polymerase. The effect of these mutations on the AHL synthesis and on the regulation of various metabolic processes in P. chlororaphis was studied.

4-Butyrolactone↗
PubMed2006

[Analysis of mechanism and relationship of GacA and RsmA, two regulators of antibiotics production in Pseudomonas sp. M18].

In previous study, it has already been confirmed that the wild type strain of Pseudomonas sp. M18 isolated from the agricultural soil can produce two antifungal agents phenazine-1-carboxylic acid (PCA) and pyoluteorin (Plt). Biosynthesis and secretion of these secondary metabolites contribute to its biological control and suppression of soilborne pathogenic fungi. As main regulators, GacA and RsmA differentially exert global regulation on production of PCA and Plt, respectively. In order to study the regulatory mechanism of secondary metabolites production in Pseudomonas sp. M18, a gacArsmA double mutant, designated as M18GR, was constructed with insertional mutation. Then, the mutant M18G, M18R, M18GR and the wild type strain M18 were inoculated into PPM or King's medium B (KMB), respectively. During cultivation of strain M18 and its derivatives, their PCA and Pit were respectively detected with High Performance Liquid Chromatography (HPLC). The results showed that PCA production in the mutant M18GR was lower than that in the mutant M18G and higher than that in the mutant M18R. Plt production in the mutant M18GR was, however, much less than that in the mutant M18R and much more than that in the strain M18 and the mutant M18G. With these observations, it is tempting to suggest that biosynthesis of PCA and Plt regulated by GacA or RsmA seem to occur at posttranscriptional level, not at transcriptional level. This regulation on secondary metabolites seems to be indirectly mediated by other unknown factors. Meanwhile, based on the construction of two translational fusions, gacA'-'lacZ and rsmA'-'lacZ, the assay of beta-galactosidase activities in KMB medium indicated that both GacA and RsmA did not have autoinduction of their own gene expression, respectively. Although GacA did not influence expression of the rsmA gene, RsmA could exert some positive influence on the gacA gene expression in Pseudomonas sp. M18.

Antifungal Agents↗
PubMedDate not supplied

[The interaction of alkylating derivatives of oligodeoxyribonucleotides and their methylphosphonate analogs with Mycoplasma cells].

Alkylating derivatives of decathymidylates and methylphosphonate analogs of oligodeoxyribonucleotides (MPAO) were studied for their interaction with cells of Acholeplasma laidlawii PG-8, Mycoplasma capricolum California Kid, M. pneumoniae FH and phytopathogenic strain (St. 118). It is shown that MPAO of octa- and hexadecathymidylates as well as decathymidylates 3'-terminal modified by phenazine and cholesterol groupings are sorbed by mycoplasma cells and can penetrate inside the cells. Efficiency of binding of alkylating derivatives and MPAO with mycoplasma cells depends on interaction time of reagents, their concentration in the reaction mixture and temperature.

Acholeplasma laidlawii↗
PubMed1990

Nitric oxide is inactivated by the bacterial pigment pyocyanin.

Pyocyanin is a phenazine pigment produced by the bacterium Pseudomonas aeruginosa and found in human lung secretions. Micromolar concentrations of pyocyanin inhibited the bioactivity of endothelium-derived relaxing factor (EDRF) generated from bovine pulmonary-artery endothelium in response to bradykinin. This inhibition was reversed by perfusing the EDRF-bioassay system with pyocyanin-free buffer for 15 min, but persisted in the presence of superoxide dismutase (20 units/ml). When nitric oxide, the major component of EDRF, was passed into an aqueous solution of pyocyanin in the absence of O2, a rapid colour change occurred from blue to pink; m.s. analysis of the products showed that the pyocyanin had been converted into a nitrosylated species.

Animals↗