53 research outputs found
Towards novel difluorinated sugar mimetrics; syntheses and conformational analyses of highly-functionalised difluorinated cyclooctenones
Highly-functionalised difluorinated cyclooctenones were synthesised from trifluoroethanol using either metallated difluoroenol acetal or carbamate chemistry, followed by a [2,3]-Wittig rearrangement or aldol reaction. Efficient RCM reactions afforded the title compounds which showed rather restricted fluxional behaviour by VT 19F NMR. Topological characterisation by molecular modelling and NOESY/ROESY experiments offered a number of challenges, but allowed the identification of two favoured boat-chair conformers which interconverted by pseudorotation with relatively large activation barriers
Mechanisms of Tolerance and Resistance to Chlorhexidine in Clinical Strains of Klebsiella pneumoniae Producers of Carbapenemase: Role of New Type II Toxin-Antitoxin System, PemIK
Although the failure of antibiotic treatment is normally attributed to resistance, tolerance
and persistence display a significant role in the lack of response to antibiotics. Due to the fact that
several nosocomial pathogens show a high level of tolerance and/or resistance to chlorhexidine,
in this study we analyzed the molecular mechanisms associated with chlorhexidine adaptation in two
clinical strains of Klebsiella pneumoniae by phenotypic and transcriptomic studies. These two strains
belong to ST258-KPC3 (high-risk clone carrying β-lactamase KPC3) and ST846-OXA48 (low-risk
clone carrying β-lactamase OXA48). Our results showed that the K. pneumoniae ST258-KPC3CA
and ST846-OXA48CA strains exhibited a different behavior under chlorhexidine (CHLX) pressure,
adapting to this biocide through resistance and tolerance mechanisms, respectively. Furthermore,
the appearance of cross-resistance to colistin was observed in the ST846-OXA48CA strain (tolerant to
CHLX), using the broth microdilution method. Interestingly, this ST846-OXA48CA isolate contained
a plasmid that encodes a novel type II toxin/antitoxin (TA) system, PemI/PemK. We characterized this
PemI/PemK TA system by cloning both genes into the IPTG-inducible pCA24N plasmid, and found
their role in persistence and biofilm formation. Accordingly, the ST846-OXA48CA strain showed
a persistence biphasic curve in the presence of a chlorhexidine-imipenem combination, and these
results were confirmed by the enzymatic assay (WST-1).The State Plan for R+D+I 2013–2016 National Plan for Scientific Research, Technological Development and Innovation 2008–2011 PI16/01163 and PI19/00878ISCIII-Deputy General Directorate for Evaluation and Promotion of Research - European Regional Development Fund “A way of Making Europe” and Instituto de Salud Carlos III FEDER, Spanish Network for the Research in Infectious Diseases REIPI, RD16/0016/0001, RD16/CIII/0004/0002 and RD16/0016/0006The Study Group on Mechanisms of Action and Resistance to Antimicrobials, GEMAR
Relationship Between the Quorum Network (Sensing/Quenching) and Clinical Features of Pneumonia and Bacteraemia Caused by A. baumannii
Acinetobacter baumannii (Ab) is one of the most important pathogens associated
with nosocomial infections, especially pneumonia. Interest in the Quorum network,
i.e., Quorum Sensing (QS)/Quorum Quenching (QQ), in this pathogen has grown
in recent years. The Quorum network plays an important role in regulating diverse
virulence factors such as surface motility and bacterial competition through the
type VI secretion system (T6SS), which is associated with bacterial invasiveness.
In the present study, we investigated 30 clinical strains of A. baumannii isolated in
the “II Spanish Study of A. baumannii GEIH-REIPI 2000-2010” (Genbank Umbrella
Bioproject PRJNA422585), a multicentre study describing the relationship between the
Quorum network in A. baumannii and the development of pneumonia and associated
bacteraemia. Expression of the aidA gene (encoding the AidA protein, QQ enzyme) was
lower (P < 0.001) in strains of A. baumannii isolated from patients with bacteraemic
pneumonia than in strains isolated from patients with non-bacteraemic pneumonia.
Moreover, aidA expression in the first type of strain was not regulated in the presence
of environmental stress factors such as the 3-oxo-C12-HSL molecule (substrate of AidA
protein, QQ activation) or H2O2 (inhibitor of AidA protein, QS activation). However, in the
A. baumannii strains isolated from patients with non-bacteraemic pneumonia, aidA gene
expression was regulated by stressors such as 3-oxo-C12-HSL and H2O2. In an in vivo
Galleria mellonella model of A. baumannii infection, the A. baumannii ATCC 17978 strain
was associated with higher mortality (100% at 24 h) than the mutant, abaI-deficient, strain (carrying a synthetase enzyme of Acyl homoserine lactone molecules) (70% at 24 h).
These data suggest that the QS (abaR and abaI genes)/QQ (aidA gene) network affects
the development of secondary bacteraemia in pneumonia patients and also the virulence
of A. baumannii.National Plan for Scientific ResearchTechnological Development and Innovation PI16/01163ISCIII-Deputy General Directorate for Evaluation and Promotion of Research-European Regional Development Fund A way of Making EuropeInstituto de Salud Carlos IIIMiguel Servet Research Programme SERGAS and ISCIIIXunta de Galicia (GAIN, Axencia de Innovación
Relationship Between Quorum Sensing and Secretion Systems
Quorum sensing (QS) is a communication mechanism between bacteria that allows specific processes to be controlled, such as biofilm formation, virulence factor expression, production of secondary metabolites and stress adaptation mechanisms such as bacterial competition systems including secretion systems (SS). These SS have an important role in bacterial communication. SS are ubiquitous; they are present in both Gram-negative and Gram-positive bacteria and in Mycobacterium sp. To date, 8 types of SS have been described (T1SS, T2SS, T3SS, T4SS, T5SS, T6SS, T7SS, and T9SS). They have global functions such as the transport of proteases, lipases, adhesins, heme-binding proteins, and amidases, and specific functions such as the synthesis of proteins in host cells, adaptation to the environment, the secretion of effectors to establish an infectious niche, transfer, absorption and release of DNA, translocation of effector proteins or DNA and autotransporter secretion. All of these functions can contribute to virulence and pathogenesis. In this review, we describe the known types of SS and discuss the ones that have been shown to be regulated by QS. Due to the large amount of information about this topic in some pathogens, we focus mainly on Pseudomonas aeruginosa and Vibrio spp
“Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels
New corrosion inhibitors for evaporative cooling systems
Corrosion of heat exchangers and installations in evaporative cooling systems is a serious problem of industry, as it may lead to increased maintenance effort, damages, up to plant shut-down causing high cost. Furthermore, there may be a high environmental impact due to the discharge of blow-down water containing heavy metals or hazardous compounds, which may enter the water system via leakages.
State of the art corrosion inhibitor programs are based on phosphate, phosphonates, zinc and combinations thereof. Although generally satisfying control of corrosion can be achieved, all programs suffer more or less severe drawbacks, such as lack of biodegradability, content of heavy metals or necessity of pH control combined with acid dosage. Consequently, there is a need of corrosion inhibitors having an improved environmental profile and/or an improved performance. This paper shows the first results of two newly developed corrosion inhibitors. Both molecules are based on modified organic acids, free of heavy metals, one additionally doesn’t contain phosphorous.
Corrosion tests have been carried out with carbon steel specimen in dependence of inhibitor concentration, water composition and water temperature. Electrochemical methods, e.g. voltammetrie and polarization resistance, were applied as well as beaker tests and long term tests in cooling circuit simulating devices. Furthermore, the anti-scaling efficiency of the new inhibitors was studied.
The results of the corrosion tests clearly show an excellent efficiency of both substances, that meets the performance of commercially available corrosion inhibitors. In addition to this the phosphorous containing molecule shows a very good inhibition of calcium carbonate scaling, similar or even better compared to the performance of modern polycarboxylates. Thus, it could be the backbone of a complete treatment program for cooling systems. The second corrosion inhibitor could be applied in phosphorous and heavy metal free corrosion inhibition programs
Tetrahydrofuran alpha-azido esters: Precursors of anomeric alpha-amino acid monomers via radical bromination
A general route for the synthesis of tetrahydrofuran α-azido esters as the equivalent of monomeric furanose anomeric α-amino acids is described. Highly selective radical bromination of a range of suitably protected carbohydrate C-glycosyl derivatives affords bromo-esters which undergo efficient displacement by azide to give anomeric α-amino acid derivatives
Photobromination of a bicyclic mimic of alpha-L-fucose; Components for a combinatorial library of rigid fucose analogues
Photobromination of a rigid bicyclic α-L-fucose analogue, affords a single crystalline monobromide, the structure of which is confirmed by X-ray cvystallography. Displacement of this bromide with azide proceeds with inversion to a single crystalline azide, which on reduction leads to an amine and thence to a range of novel substituted rigid α-L-fucose derivatives. Hydrolysis of the bromide leads to two isomenc alcohols via an acetate migration. Both the bromide and amine may prove to be useful intermediates for the generation of libraries of mimics of L-fucose
Synthesis of seven- and eight-membered carbasugar analogs via ring-closing metathesis and their inhibitory activities toward glycosidases
An expeditious and efficient synthesis of new enantiopure polyhydroxylated seven- and eight-membered carbocycles is described starting from 2,3.5-tri-O-benzyl-D-arabinose. The key cyclization step involves ring closing metathesis of 1,8- and 1,9-dienes using Grubbs' catalyst. All of the new carbasugar analogs synthesized were evaluated as glycosidase inhibitors. Contrary to Our expectations, (1 S,2S,3R,4R,5R)-1-(hydroxymethyl)-cyclohepta-1,2,3,4,5-pentol which has the beta-D-mannopyranose configuration for C(1)-C(5) inhibits alpha- and beta-glucosidases, whereas its diepimer (1S,2S,3R,4S,5S)-1-(hydroxymethyl)-cyclohepta-1,2,3,4,5-pentol, which has the alpha-D-glucopyranose configuration, is not recognised by these enzymes. (C) 2002 Elsevier Science Ltd. All rights reserved
Cystic fibrosis and diabetes: isoLAB and isoDAB, enantiomeric carbon-branched pyrrolidine iminosugars
Acetonides are the only protecting groups used in the syntheses of isoDAB from d-ribose and of isoLAB from d-tagatose. isoDAB is a potent and highly specific competitive α-glucosidase inhibitor (for rice α-glucosidase, Ki = 4 μM for isoDAB compared to K i 14 μM for DAB). isoDAB is not an - whereas DAB is a potent - inhibitor of glycogen phosphorylase. This is the first example of any potent inhibition of glycosidases by a carbon-branched iminosugar pyrrolidine. Although isoLAB shows no inhibition of any glycosidase, preliminary experiments suggest that isoLAB partially rescues the defective F508del-CFTR function and so may have a role in the study of cystic fibrosis. © 2010 Elsevier Ltd. All rights reserved
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