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Sadlej J.,University of Warsaw | Sadlej J.,Polish National Medicines Institute | Dobrowolski J.C.,Polish National Medicines Institute | Dobrowolski J.C.,Industrial Chemistry Research Institute | Rode J.E.,Industrial Chemistry Research Institute
Chemical Society Reviews | Year: 2010

Most of the research in contemporary physical chemistry is devoted to the development of methods that extend our understanding, interpretation, and capacity to predict structural properties and dynamic behavior of molecules. The optical and magnetic spectroscopies, as well as diffraction techniques, are the principal methods for studying properties of molecules, biomolecules, and biopolymers of which the vast majority are chiral. On the other hand, information on molecular configuration can be obtained mainly from optical spectroscopies because other well-established spectroscopic techniques used for structural investigations, such as crystallographic, ESR, and NMR methods, do not allow for registration of signals from an individual conformer owing to intrinsic slow response to structural changes. This is the reason why the optical spectroscopy methods, based on natural chiroptical phenomena, have become so important and their renaissance in the last decade is noticed. Vibrational circular dichroism (VCD) spectroscopy is one such chiroptical technique that sheds new light on many important phenomena studied intensively. We provide an overview of recent theoretical predictions and innovative VCD observations of chirality transfer (called by other authors "induced chirality") from a chiral molecule to an achiral one as a result of hydrogen bond interactions between them. In this tutorial review we search for answers as to whether we can obtain further information about intermolecular interactions using the VCD technique. In our opinion this technique has opened new horizons for both understanding and monitoring intermolecular interactions and it could be used as a relatively new and powerful physicochemical method. © 2010 The Royal Society of Chemistry.

Sadowy E.,Polish National Medicines Institute | Luczkiewicz A.,Technical University of Gdansk
BMC Microbiology | Year: 2014

Background: Enterococci, ubiquitous colonizers of humans and other animals, play an increasingly important role in health-care associated infections (HAIs). It is believed that the recent evolution of two clinically relevant species, Enterococcus faecalis and Enterococcus faecium occurred in a big part in a hospital environment, leading to formation of high-risk enterococcal clonal complexes (HiRECCs), which combine multidrug resistance with increased pathogenicity and epidemicity. The aim of this study was to establish the species composition in wastewater, its marine recipient as well as a river estuary and to investigate the antimicrobial susceptibility of collected isolates. Molecular methods were additionally applied to test the presence of HiRRECC-related E. faecium. Results: Two wastewater treatment plants (WWTPs), their marine outfalls and Vistula river that influence significantly the quality of waters in Gulf of Gdansk were sampled to investigate the presence of Enterococcus spp. Four-hundred-twenty-eight isolates were obtained, including E. faecium (244 isolates, 57.0%), E. hirae (113 isolates, 26.4%) and E. faecalis (63 isolates, 14.7%); other species (E. gallinarum/casseliflavus, E. durans and E. avium) accounted for 1.9%. Antimicrobial susceptibility testing revealed the presence of isolates resistant to erythromycin, tetracycline, amipicillin, fluoroquinolones and aminoglycosides (high-level resistance), especially among E. faecium, where such isolates were usually characterized by multilocus sequence types associated with nosocomial lineages 17, 18 and 78 of this species representing HiRECC, formerly called CC17. These isolates not only carried several resistance determinants but were also enriched in genes encoding pathogenicity factors (Esp, pili) and genes associated with mobile genetic elements (MGE), a feature also typical for nosocomial HiRECC. Conclusions: Our data show that WWTPs constitute an important source of enterococcal strains carrying antimicrobial resistance determinants, often associated with the presence of MGE, for the recipient water environment, thus increasing a pool of such genes for other organisms. The presence of HiRECCs in wastewaters and marine/river environment may indicate that adaptations gained in hospitals may be also beneficial for survival of such clones in other settings. There is an obvious need to monitor the release and spread of such strains in order to elucidate better ways to curb their dissemination. © 2014 Sadowy and Luczkiewicz; licensee BioMed Central Ltd.

Obszanska K.,Polish National Medicines Institute
Virulence | Year: 2012

Streptococcus pyogenes (GAS) is a human pathogen that causes millions of infections worldwide. Comparison between GAS strains isolated in different laboratories all over the world is often difficult. Three usually used methods have either low resolution (emm typing), are expensive (MLST) or time- and labor-consuming (PFGE). Our laboratory recently developed new, inexpensive methods of GAS typing-VF (virulence factor profiling) and PP (phage profiling). To improve the typing scheme developed for GAS, we recently proposed a new typing method. Here we present detailed protocol for MLVF analysis.

Sadlej-Sosnowska N.,Polish National Medicines Institute
Physical Chemistry Chemical Physics | Year: 2015

The effect of a homogeneous static electric field on the Li-benzene complex in two configurations, one with a larger Li-C6H6 distance ("loose") and one with a shorter distance ("tight"), has been investigated. The electric field has the same orientation as the direction of the dipole moments of the complexes. When the direction of the field intensity vector was the same as that of the dipole moment vector, optimization of the complex's geometry in one configuration resulted in switching it to the other one. Reversing the direction of the field then transformed the other configuration back to the original one. This switching behavior was observed beginning with the loose configuration and with the tight configuration. The geometrical and electronic parameters of the complex after four steps of the reversible switching have been calculated for a selected field intensity of 0.005 atomic units (a.u.), that is 0.257 V Å-1. © 2015 the Owner Societies.

Sadowy E.,Polish National Medicines Institute | Matynia B.,Polish National Medicines Institute | Hryniewicz W.,Polish National Medicines Institute
Journal of Antimicrobial Chemotherapy | Year: 2010

Objectives: To analyse Streptococcus agalactiae (group B Streptococcus; GBS) isolates collected in Poland from various human infections and carriage in respect of their clonality, distribution of virulence factors and antimicrobial resistance determinants, including the detection of transposons involved in the dissemination of antimicrobial resistance. Methods: One hundred and fourteen GBS isolates were analysed by multilocus sequence typing (MLST), serotyping and detection of alp genes of the α-like-protein (Alp) family. Determinants of resistance to macrolides and tetracycline, and associated transposons, were detected by PCR and analysed by sequencing. Results: GBS isolates represented 30 different sequence types (STs), grouped in four clonal complexes (CCs), and belonged to seven serotypes. Serotype III was predominant (36.0%), followed by Ia, V, Ib, II, IV and VI. The most common alp genes were rib (26.3%) and alp1/alp5 (23.7%). The bac gene encoding the β-compound of the surface C-protein was present in 17.5% of isolates. Erythromycin resistance (18.4% of isolates) was found in all CCs, but was associated with serotype V and ST1. The most prevalent determinant of resistance was erm(B), usually located on the Tn3872-like transposon. Several changes were observed in the regulatory region of erm(B), some of them resulting in elevated ketolide MICs. Resistance to tetracycline was ubiquitous (91.2%) and its most common determinant was tet(M), occurring in several variants that were typically carried on Tn916-family transposons. Conclusions: Analysis of bacterial serotypes, alp genes and antimicrobial resistance determinants in the background of MLST-based population structure strengthened evidence of the importance of horizontal gene transfer in GBS evolution. © The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Gnyszka A.,Polish National Medicines Institute | Jastrzebski Z.,Polish National Medicines Institute | Flis S.,Polish National Medicines Institute
Anticancer Research | Year: 2013

The DNA methyltransferase (DNMT) inhibitors azacytidine and decitabine are the most successful epigenetic drugs to date and are still the most widely used as epigenetic modulators, even though their application for oncological diseases is restricted by their relative toxicity and poor chemical stability. Zebularine (1-(β-D-ribofuranosyl)-1,2- dihydropyrimidin-2-one), a more stable and less toxic cytidine analog, is another inhibitor of DNMT with concomitant inhibitory activity towards cytidine deaminase. Unfortunately, there is no new information related to the possible clinical applications of zebularine. Although many new inhibitors of DNMT have been identified, none of them can so far replace azacytidine, decitabine and, to a lesser degree, zebularine. This review summarizes the current data and knowledge about azacytidine, decitabine and zebularine, and their role in present and possible future epigenetic cancer therapy. We also discuss the molecular modes of action of these agents with consideration of their different toxicities and demethylation profiles, reflecting their complex and partially overlapping biological effects.

Carboxylic acids based on exo-substituted tria-, penta-, heptafulvenes and ethylene (acrylic acids) were examined in order to determine if they are more sensitive to the substituent effect than benzoic acid - the system originally employed by Hammett. In order to accomplish this task, all possible structural isomers of benzoic acid, tria-, penta- and heptafulvene-based carboxylic acids, acrylic and methacrylic acids substituted by 13 substiuents (BH2, CHO, CN, COCN, NO2, CF3, Me, Cl, F, OH, OMe, NH 2 and NMe2) were optimized at the B3LYP/6-311++G(d,p) level of theory, and Gibbs free energies of carboxylic group dissociation (ΔGdis) were calculated. These energies were subsequently intercorrelated, and from the slopes of linear regressions, it was estimated which system is associated with greatest changes of ΔGdis due to substitution and thus is most sensitive to the substituent effect. It was found that all fulvene-based carboxylic acids have greater range of ΔGdis change than benzoic acid, but the largest range of change was observed in the case of acrylic and methacrylic acids. The acrylic acid as the most sensitive system to substitution could replace benzoic acid for an improved version of substituent constant used to measure pi-electron substituent effect. Copyright © 2013 John Wiley & Sons, Ltd.

Szatylowicz H.,Warsaw University of Technology | Sadlej-Sosnowska N.,Polish National Medicines Institute
Journal of Chemical Information and Modeling | Year: 2010

The energies of individual hydrogen bonds (H-bonds) in A-T and G-C Watson-Crick base pairs were calculated according to the natural bond orbital (NBO) analysis of intermolecular interactions. The extent to which individual H-bonds are helpful in holding the two base pairs together was previously investigated quantitatively by a few different approaches, and the results of the present and previous estimations were compared. The method was validated by the determination of the H-bond strength changes in A-T and G-C pairs upon the substitution of the monomer (base) by two cationic substituents; the systems for which the changes were previously anticipated based on the modifications of the H-bonds' distances. © 2010 American Chemical Society.

Borek A.L.,Polish National Medicines Institute
Virulence | Year: 2012

Streptococcus pyogenes (GAS) is a human pathogen that causes multiple infections worldwide. The pathogenic properties of GAS strains are often linked to the production of virulence factors such as toxins, proteases or DNases. Detection of virulence factors produced by GAS strains can be used to either determine pathogenic potential of the strain or as a rapid screening and typing method. We recently developed a method to detect simultaneously 20 GAS virulence factors (spd3, sdc, sdaB, sdaD, speB, spyCEP, scpA, mac, sic, speL, K, M, C, I, A, H, G, J, smeZ and ssa) in four low volume multiplex PCR reactions (Borek et al., 2011) and below we present a detailed protocol describing the method.

To obtain a status of a medicinal product, a compound possessing potential antimicrobial activity and displaying no cytotoxicity, must undergo three phases of clinical trials to prove its therapeutic efficacy, safety and quality. Properties of the compound should be based on the results of studies meeting specific criteria. Studies should be: randomized, double-blind, involving sufficient number of volunteers, concerning the infections localized in strictly defined area and caused by identified microorganisms. After the medicinal product is authorized to be on the market, clinical trials of the fourth phase are carried out to detect adverse effects, overdose symptoms, interactions of the new drug with other medicinal products and to establish characteristic of activity among groups such as children, elderly, women in pregnancy and patients suffering from other diseases, but only if the benefits of receiving treatment outweigh the risks. This article is a second part of the series associated with searching for new antibacterial agents and it relates to performance of clinical trials and the new compounds belonging to the class of beta-lactams. Among the 9 presented compounds, candidates to become medicinal products, two belong to the cephalosporins (CXA-101, S-649266), one to carbapenems (razupenem), three to monobactams (BAL30072, BAL30376, MC-1) and three to beta-lactamase inhibitors (NXL-104, MK-7655, ME1071).

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