15 research outputs found
Revisiting the thiosemicarbazonecopper(II) reaction with glutathione. Activity against colorectal carcinoma cell lines
Thiosemicarbazones (TSCs), and their copper derivatives, have been extensively studied mainly due to the
potential applications as antitumor compounds. A part of the biological activity of the TSC-CuII complexes rests
on their reactivity against cell reductants, as glutathione (GSH). The present paper describes the structure of the
[Cu(PTSC)(ONO2)]n compound (1) (HPTSC =pyridine-2-carbaldehyde thiosemicarbazone) and its spectroscopic
and magnetic properties. ESI studies performed on the reaction of GSH with 1 and the analogous [{Cu
(PTSC*)(ONO2)}2] derivative (2, HPTSC* =pyridine-2-carbaldehyde 4N-methylthiosemicarbazone) show the
absence of peaks related with TSC-Cu-GSH species. However GSH-Cu ones are detected, in good agreement with
the release of CuI ions after reduction in the experimental conditions. The reactivity of 1 and 2 with cytochrome
c and myoglobin and their activities against HT-29 and SW-480 colon carcinoma cell lines are compared with
those shown by the free HPTSC and HPTSC* ligands.Obra Social “la
Caixa” (OSLC-2012-007), Ministerio de EconomĂa y Competitividad and
FEDER funds (CTQ2013-48937-C2-1-P, CTQ2015-70371-REDT,
MAT2015-66441-P, BIO2015-67358-C2-2-P), Junta de Castilla y LeĂłn
(BU237U13), Gerencia Regional de Salud, ConsejerĂa de Sanidad, Junta
de Castilla y LeĂłn (GRS 1023/A/14), the Basque Government (project
IT-779-13
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From insect to man: Photorhabdus sheds light on the emergence of human pathogenicity
Photorhabdus are highly effective insect pathogenic bacteria that exist in a mutualistic relationship with Heterorhabditid nematodes. Unlike other members of the genus, Photorhabdus asymbiotica can also infect humans. Most Photorhabdus cannot replicate above 34°C, limiting their host-range to poikilothermic invertebrates. In contrast, P. asymbiotica must necessarily be able to replicate at 37°C or above. Many well-studied mammalian pathogens use the elevated temperature of their host as a signal to regulate the necessary changes in gene expression required for infection. Here we use RNA-seq, proteomics and phenotype microarrays to examine temperature dependent differences in transcription, translation and phenotype of P. asymbiotica at 28°C versus 37°C, relevant to the insect or human hosts respectively. Our findings reveal relatively few temperature dependant differences in gene expression. There is however a striking difference in metabolism at 37°C, with a significant reduction in the range of carbon and nitrogen sources that otherwise support respiration at 28°C. We propose that the key adaptation that enables P. asymbiotica to infect humans is to aggressively acquire amino acids, peptides and other nutrients from the human host, employing a so called “nutritional virulence” strategy. This would simultaneously cripple the host immune response while providing nutrients sufficient for reproduction. This might explain the severity of ulcerated lesions observed in clinical cases of Photorhabdosis. Furthermore, while P. asymbiotica can invade mammalian cells they must also resist immediate killing by humoral immunity components in serum. We observed an increase in the production of the insect Phenol-oxidase inhibitor Rhabduscin normally deployed to inhibit the melanisation immune cascade. Crucially we demonstrated this molecule also facilitates protection against killing by the alternative human complement pathway
Xenortide biosynthesis by entomopathogenic xenorhabdus nematophila
The biosynthesis gene cluster of the xenortides and a new derivative, xenortide D, which is produced in only trace amounts, was identified in Xenorhabdus nematophila. The structure of xenortide D was elucidated using a combination of labeling experiments followed by MS analysis and was confirmed by synthesis. Bioactivity tests revealed a weak activity of tryptamine-carrying xenortides against Plasmodium falciparum and Trypanosoma brucei
Synthesis of szentiamide, a depsipeptide from entomopathogenic Xenorhabdus szentirmaii with activity against Plasmodium falciparum
The synthesis of the recently characterized depsipeptide szentiamide (1), which is produced by the entomopathogenic bacterium Xenorhabdus szentirmaii, is described. Whereas no biological activity was previously identified for 1, the material derived from the efficient synthesis enabled additional bioactivity tests leading to the identification of a notable activity against insect cells and Plasmodium falciparum, the causative agent of malaria
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Insect-specific production of new gameXpeptides in photorhabdus luminescensTTO1, widespread natural products in entomopathogenic bacteria
Discovery of new natural products by heterologous expression reaches its limits, especially when specific building blocks are missing in the heterologous host or the production medium. Here, we describe the insect-specific production of the new GameXPeptides E–H (5–8) from Photorhabdus luminescens TTO1, which can be produced heterologously from expression of the GameXPeptide synthetase GxpS only upon supplementation of the production media with the missing building blocks, and thus must be regarded as the true natural products under natural conditions
Xenortide Biosynthesis by Entomopathogenic <i>Xenorhabdus nematophila</i>
The biosynthesis gene cluster of
the xenortides and a new derivative,
xenortide D, which is produced in only trace amounts, was identified
in <i>Xenorhabdus nematophila</i>. The structure of xenortide
D was elucidated using a combination of labeling experiments followed
by MS analysis and was confirmed by synthesis. Bioactivity tests revealed
a weak activity of tryptamine-carrying xenortides against <i>Plasmodium falciparum</i> and <i>Trypanosoma brucei</i>
Rhabdopeptides as insect-specific virulence factors from entomopathogenic bacteria
Six novel linear peptides, named "rhabdopeptides", have been identified in the entomopathogenic bacterium Xenorhabdus nematophila after the discovery of the corresponding rdp gene cluster by using a promoter trap strategy for the detection of insect-inducible genes. The structures of these rhabdopeptides were deduced from labeling experiments combined with detailed MS analysis. Detailed analysis of an rdp mutant revealed that these compounds participate in virulence towards insects and are produced upon bacterial infection of a suitable insect host. Furthermore, two additional rhabdopeptide derivatives produced by Xenorhabdus cabanillasii were isolated, these showed activity against insect hemocytes thereby confirming the virulence of this novel class of compounds
Neutral Loss Fragmentation Pattern Based Screening for Arginine-Rich Natural Products in <i>Xenorhabdus</i> and <i>Photorhabdus</i>
Although sharing a certain degree of structural uniformity,
natural
product classes exhibit variable functionalities such as different
amino acid or acyl residues. During collision induced dissociation,
some natural products exhibit a conserved fragmentation pattern close
to the precursor ion. The observed fragments result from a shared
set of neutral losses, creating a unique fragmentation pattern, which
can be used as a fingerprint for members of these natural product
classes. The culture supernatants of 69 strains of the entomopathogenic
bacteria <i>Photorhabdus</i> and <i>Xenorhabdus</i> were analyzed by MALDI-MS<sup>2</sup>, and a database comprising
MS<sup>2</sup> data from each strain was established. This database
was scanned for concordant fragmentation patterns of different compounds
using a customized software, focusing on relative mass differences
of the fragment ions to their precursor ion. A novel group of related
natural products comprising 25 different arginine-rich peptides from
16 different strains was identified due to its characteristic neutral
loss fragmentation pattern, and the structures of eight compounds
were elucidated. Two biosynthesis gene clusters encoding nonribosomal
peptide synthetases were identified, emphasizing the possibility to
identify a group of structurally and biosynthetically related natural
products based on their neutral loss fragmentation pattern
The genus <i>Photorhabdus</i> contains three predominant species.
<p>A stylized representation of a previous six gene MLST phylogeny (<i>adk</i>, <i>ghd</i>, <i>mdk</i>, <i>ndh</i>, <i>pgm</i> and <i>recA</i>) of <i>Photorhabdus</i> (adapted from [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0144937#pone.0144937.ref005" target="_blank">5</a>]) is shown. The grey areas indicate species that consist of multiple strains, the majority of which are unable to grow above 34°C, with only a few <i>P</i>. <i>luminescens</i> strains capable of growth at temperatures up to 37°C. Example strains are <i>P</i>. <i>luminescens</i><sup>TT01</sup> and <i>P</i>. <i>temperata</i><sup>K122</sup>. The clinical strains adapted to 37°C are boxed. The stars and circles indicate the potential historical timing of temperature adaptation, which could have occurred ancestrally (star) or independently (circles) in different geographical isolates.</p