Moscow, Russia
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Okorochenkov S.A.,Lomonosov Moscow University of Fine Chemical Technology | Zheltukhina G.A.,Lomonosov Moscow University of Fine Chemical Technology | Mirchink E.P.,Russian Academy of Medical Sciences | Isakova E.B.,Russian Academy of Medical Sciences | And 2 more authors.
Chemical Biology and Drug Design | Year: 2013

The increasing prevalence of antibiotic-resistant bacterial strains has necessitated the synthesis of novel antibacterial agents. It was previously shown that naturally occurring metalloporphyrin hemin possesses dark antibacterial activity against Gram-positive bacteria. To improve hemin antibacterial activity, we synthesized a number of hemin conjugates with amino acids and branched peptides. Arginine-containing hemin conjugates demonstrated high antibacterial activity against Gram-positive bacteria including methicillin- and vancomycin-resistant strains in vitro. Most of the synthesized conjugates showed low toxicity against human erythrocytes and leukocytes. © 2013 John Wiley & Sons A/S.

Okorochenkov S.A.,Lomonosov Moscow University of Fine Chemical Technology | Zheltukhina G.A.,Lomonosov Moscow University of Fine Chemical Technology | Roginsky V.A.,RAS Semenov Institute of Chemical Physics | Nossik N.N.,Russian Academy of Medical Sciences | And 2 more authors.
Journal of Porphyrins and Phthalocyanines | Year: 2012

We synthesized a series of hemin derivatives (HDs) substituted by residues of amino acids and peptides at either one or two propionic-acid residues, and studied the virucidal activity of the compounds obtained against herpes simplex virus. Compounds 6,7-bis-(methyl ester N 0 L-seryl)-protohemin (IX) (2) and 6,7-bis-[methyl ester N 0-L-arginyl)-protohemin (IX) (6) shown the highest virucidal activity. We also investigated the interaction between HDs and lipid-membrane components as a possible mechanism of virucidal action. A model system including Clark's electrode and a micellar solution of methyl linoleate was used to quantitatively assess the capability of HDs to catalyze the oxidation of polyunsaturated fatty acids as components of lipid membranes. Another model system including liposomes that consisted of dioleoylphosphatydylcholine and was loaded with the fluorescent dye carboxyfluorescein was employed to examine the effect of HDs on lipid-membrane permeability. The kinetics and efficacy of increasing liposome-membrane permeability on exposure to HDs appeared to depend on the nature of the substituents in the HDs. The findings are strongly suggestive of the presence of two different modes of interaction between an HD and the lipid membrane, i.e. oxidative and non-oxidative mechanisms possibly underlie the virucidal action of HDs. © 2012 World Scientific Publishing Company.

Ponomaryov K.A.,Moscow State University | Zheltukhina G.A.,Moscow State University | Sidomk K.V.,Research Institute for Genetics and Selection of Industrial Microorganisms | Nebolsin V.E.,LTD Pharmenterprises
Macroheterocycles | Year: 2013

Luciferases are now widely used in studies of molecular genetics (gene-reporters), in biochemical assays in wide screening of chemical contamination of the environment (ecology), in genetic engineering works (selection), etc. Phe high sensitivity and ease of detection of the light signal with a help of luminometer or scintillation counter, a direct proportionality between the amount of the enzyme luciferase and intensity of bioluminescence in a wide range (up to ten orders of magnitude), the ability to measure with equal success the enzyme activity in vitro and in vivo, without the destruction of the cells, and other benefts determine the application of luciferases of the bacterial senes is (genes lux) and eukaryotic (genes luc) origin in various genetic and biochemical tests, such as the search and analysis of the promoter and regulatory regions of DNA, by screening of DNA-tropic compounds, by measurement of APP and other trace. Puxbiosensors are widely used in studies of genetic engineering and biotechnology, as well as for the detection of toxic agents (environmental monitoring).[13] Previously, we have shown that the derivatives of hemin (DH) have expressed peroxidase activity/61 and they are able to catalyse the oxidation of the reduced biological substrates (NADH) by hydrogen peroxide and by a model lipophilic tert-butyl hydroperoxide. In continuation of these studies the DH were demonstrated to catalyze the oxidation of polyunsaturated fatty acids (PUFAs) In this case the calculated and indirect experimental methods with suffcient reliability the PUPA hydroperoxides were shown to participate in the chain oxidation catalysed by DH.[7] Po develop this work the studies of creation of the best synthetic methods of amino acid and peptide DH are under way in our laboratory.[89] Antibacterial Activity of Hemin Conjugates Among the synthesized DH there were identifed substances such as conjugates of hemin with esters of amino acids, which have strong antibacterial activity against Gram-positive bacteria, including drug-resistant strains of Staphylococcus aureus. Ability of some of the synthesized DH to model the peroxidase enzyme functions, to increase the lipid per oxidation in the lipid membrane may determine the antimicrobial activity of DH.[10] Considering the presence of bacteria lipids containing PUFAs in the cell membranes, we have undertook the experiment, the purpose of which was to confrm the probability of involvement of reactive oxygen species (peroxides) in the interaction of DH with live bacteria, which can lead to the destruction of its membrane. Here, the degree of oxidative stress was determined by the known method,[11] using the bacterium E. coli K-12, containing hybrid plasmids, which are embedded in the genes of luminous bacteria and encoding luciferase and the reductase, which are highly sensitive to hydrogen peroxide (luxbiosensors). The threshold sensitivity of the biosensor with PkatG to hydrogen peroxide is about 5.10-6 M, which is about 10 times higher than the intracellular concentration of hydrogen peroxide (5.10-7 M), formed in the process of breathing.[11] As a result it was shown that the interaction of DH with live bacterium E. coli K-12 is accompanied by accumulation of peroxides. Thus, after 18 hours the concentration of peroxide was signifcant and greater than 10-3 M, in some cases even at submicromolar concentrations. Amino acid derivatives Hemin 1, 2 and 3 were synthesized according to previously described methods.[8] Thus, when using lux biosensor the oxidative stress as a part of DH antibacterial mechanism was confrmed at the interaction the living bacteria, what is in accordance with the catalytic activity at the oxidation of organic substrates by DH, identifed earlier by physical and chemical methods. © ISUCT Publishing.

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