RAS Gause Institute of New Antibiotics
RAS Gause Institute of New Antibiotics
Danilenko V.N.,Vavilov Institute of General Genetics |
Osolodkin D.I.,Moscow State University |
Lakatosh S.A.,RAS Gause Institute of New Antibiotics |
Preobrazhenskaya M.N.,RAS Gause Institute of New Antibiotics |
Shtil A.A.,Research Center for Biotechnology of Antibiotics
Current Topics in Medicinal Chemistry | Year: 2011
Signaling through protein kinases is an evolutionary conserved, widespread language of biological regulation. The eukaryotic type serine-threonine protein kinases (STPKs) found in normal human microbiote and in pathogenic bacteria play a key role in regulation of microbial survival, virulence and pathogenicity. Therefore, down-regulation of bacterial STPKs emerges as an attractive approach to cure infections. In this review we focused on actinobacterial STPKs to demonstrate that these enzymes can be used for crystal structure studies, modeling of 3D structure, construction of test systems and design of novel chemical libraries of low molecular weight inhibitors. In particular, the prototypic pharmacological antagonists of Mycobacterium tuberculosis STPKs are perspective for development of a novel generation of drugs to combat the socially important disease. These inhibitors may modulate both actinobacterial and host STPKs and trigger programmed death of pathogenic bacteria. © 2011 Bentham Science Publishers Ltd.
Vasilchenko A.S.,Orenburg State University |
Rogozhin E.A.,RAS Gause Institute of New Antibiotics |
Valyshev A.V.,Russian Academy of Sciences
Microbial Drug Resistance | Year: 2017
Objective: The aim of this work was to purify and characterize a bacteriocin-like antimicrobial substance produced by an antagonistic active strain of Enterococcus faecium. Methods and Results: A novel bacteriocin-like inhibitory substance (BLIS) produced by the E. faecium ICIS 8 strain was purified and characterized using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and N-terminal amino acid sequencing revealed the following partial sequence: NH2-APKEKCFPKYCV. The proteinaceous nature of purified BLIS was assessed by treatment with proteolytic enzyme. Studies of the action of BLIS using bacteriological and bioluminescence assays revealed a dose-dependent inhibition of Listeria monocytogenes 88BK and Escherichia coli K12 TG1 lac:lux viability. The interaction of the BLIS with the bacterial surface led to the compensation of a negative charge value, as shown by zeta-potential measurements. Assessments of membrane integrity using fluorescent probes and atomic force microscopy revealed the permeabilization of the cellular barrier structures in both L. monocytogenes and E. Coli. Conclusion: The novel BLIS from E. faecium ICIS 8 was characterized by a unique primary peptide sequence and exerted bactericidal activity against L. monocytogenes and E. Coli by disrupting membrane integrity. © 2017, Mary Ann Liebert, Inc.
Olsufyeva E.N.,RAS Gause Institute of New Antibiotics |
Tevyashova A.N.,RAS Gause Institute of New Antibiotics
Current Topics in Medicinal Chemistry | Year: 2017
Introduction: The increased resistance of glycopeptide based antibiotics has become a serious problem for the chemotherapy of infections triggered by resistant Gram-positive bacteria. This has motivated the urgent sincere efforts to develop potent glycopeptide-based antibiotics in both academy and industry research laboratories. Understanding of the mechanism of action of natural and modified glycopeptides is considered as the basis for the rational design of compounds with valuable properties to achieve the fundamental results. Several hydrophobic glycopeptide analogues active against resistant strains were developed during the last two decades. Three drugs, namely, oritavancin, telavancin and dalbavancin were approved by FDA in 2013-2014. It was found that hydrophobic derivatives act through different mechanisms without binding with the modified target of resistant bacteria. Types: Different types of chemical modifications led to several glycopeptide analogues active against Gram-negative bacteria as advocated by in vitro studies or demonstrating potent antiviral activity in the cell models. Conclusion: A new class of glycopeptide antibiotics with potent activity against sensitive and resistant bacterial strains has been recently reported with the aim to overcome the resistance, however, there are a lot of obscure problems in the complete understanding of their mechanisms of actions. In this review, we summarized the achievements of synthetic methods devoted to the construction of new polycyclic glycopeptide antibiotics and described the studies related to their mechanism of actions. © 2017 Bentham Science Publishers.
Ponomarenko A.I.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry |
Brylev V.A.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry |
Nozhevnikova E.V.,RAS Shemyakin Ovchinnikov Institute of Bioorganic Chemistry |
Korshun V.A.,RAS Gause Institute of New Antibiotics
Current Topics in Medicinal Chemistry | Year: 2015
The combined efforts of chemistry, nanotechnology, and spectroscopy led to the development of self-assembled fluorescent DNA nanostructures, an inexhaustible source of refined and bizarre tools and powerful techniques for research and diagnostic applications. This multidisciplinary area has tremendous prospects for science and technology. © 2015 Bentham Science Publishers.
Tevyashova A.N.,RAS Gause Institute of New Antibiotics |
Olsufyeva E.N.,RAS Gause Institute of New Antibiotics
Russian Chemical Reviews | Year: 2015
The review is devoted to the latest achievements in the design of dual action antibiotics-heterodimeric (chimeric) structures based on antibacterial agents of different classes (fluoroquinolones, anthracyclines, oxazolidines, macrolides and so on). Covalent binding can make the pharmacokinetic characteristics of these molecules more predictable and improve the penetration of each component into the cell. Consequently, not only does the drug efficacy increase owing to inhibition of two targets but also the resistance to one or both antibiotics can be overcome. The theoretical grounds of elaboration, design principles and methods for the synthesis of dual action antibiotics are considered. The structures are classified according to the type of covalent spacer (cleavable or not) connecting the moieties of two agents. Dual action antibiotics with a spacer that can be cleaved in a living cell are considered as dual action prodrugs. Data on the biological action of heterodimeric compounds are presented and structure ± activity relationships are analyzed. The bibliography includes 225 references. © 2015 Russian Academy of Sciences and Turpion Ltd
Firsov A.A.,RAS Gause Institute of New Antibiotics |
Strukova E.N.,RAS Gause Institute of New Antibiotics |
Portnoy Y.A.,RAS Gause Institute of New Antibiotics |
Shlykova D.S.,RAS Gause Institute of New Antibiotics |
Zinner S.H.,Harvard University
International Journal of Antimicrobial Agents | Year: 2015
Emergence of bacterial antibiotic resistance is usually characterised either by population analysis or susceptibility testing. To compare these endpoints in their ability to demonstrate clear relationships with the ratio of 24-h area under the concentration-time curve (AUC24) to the minimum inhibitory concentration (MIC), enrichment of ciprofloxacin-resistant mutants of four clinical isolates of Pseudomonas aeruginosa was studied in an in vitro dynamic model that simulates mono-exponential pharmacokinetics of ciprofloxacin over a wide range of the AUC24/MIC ratios. Each organism was exposed to twice-daily ciprofloxacin for 3 days. Amplification of resistant mutants was monitored by plating on media with 2×, 4×, 8× and 16× MIC of ciprofloxacin. Population analysis data were expressed by the area under the bacterial mutant concentration-time curve (AUBCM). Changes in P. aeruginosa susceptibility were examined by daily MIC determinations. To account for the different susceptibilities of P. aeruginosa strains, post-exposure MICs (MICfinal) were related to the MICs determined with the starting inoculum (MICinitial). For each organism, AUC24/MIC relationships both with AUBCM and MICfinal/MICinitial were bell-shaped, but the latter were more strain-specific than the former. Using combined data on all four isolates, AUBCM showed a better correlation than MICfinal/MICinitial (r2 = 0.75 vs. r2 = 0.53). The shift of MICfinal/MICinitial relative to AUBCM vs. AUC24/MIC curves resulted in a weak correlation between AUBCM and MICfinal/MICinitial (r2 = 0.41). These data suggest that population analysis is preferable to susceptibility testing in bacterial resistance studies and that these endpoints should not be considered interchangeable. © 2015 Elsevier B.V. and the International Society of Chemotherapy.
Strukova E.N.,RAS Gause Institute of New Antibiotics |
Portnoy Y.A.,RAS Gause Institute of New Antibiotics |
Romanov A.V.,Smolensk State University |
Edelstein M.V.,Smolensk State University |
And 2 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2016
There is growing evidence of applicability of the hypothesis of the mutant selection window (MSW), i.e., the range between the MIC and the mutant prevention concentration (MPC), within which the enrichment of resistant mutants is most probable. However, it is not clear if MPC-based pharmacokinetic variables are preferable to the respective MIC-based variables as interstrain predictors of resistance. To examine the predictive power of the ratios of the area under the curve (AUC24) to the MPC and to the MIC, the selection of ciprofloxacin-resistant mutants of three Klebsiella pneumoniae strains with different MPC/MIC ratios was studied. Each organism was exposed to twice-daily ciprofloxacin for 3 days at AUC24/MIC ratios that provide peak antibiotic concentrations close to the MIC, between the MIC and the MPC, and above the MPC. Resistant K. pneumoniae mutants were intensively enriched at an AUC24/MIC ratio of 60 to 360 h (AUC24/MPC ratio from 2.5 to 15 h) but not at the lower or higher AUC24/MIC and AUC24/MPC ratios, in accordance with the MSW hypothesis. AUC24/MPC and AUC24/MIC relationships with areas under the time courses of ciprofloxacin-resistant K. pneumoniae (AUBCM) were bell shaped. These relationships predict highly variable "antimutant" AUC24/MPC ratios (20 to 290 h) compared to AUC24/MIC ratios (1,310 to 2,610 h). These findings suggest that the potential of the AUC24/MPC ratio as an interstrain predictor of K. pneumoniae resistance is lower than that of the AUC24/MIC ratio. Copyright © 2016, American Society for Microbiology. All Rights Reserved.
Avtonomova A.V.,RAS Gause Institute of New Antibiotics |
Krasnopolskaya L.M.,RAS Gause Institute of New Antibiotics
Antibiotiki i Khimioterapiya | Year: 2014
The data on the antiviral action of the Ganoderma lucidum, Lentinus edodes, Grifola frondosa, Agaricus brasiliensis and other basidiomycetes metabolites are summurized. The metabolites of these species of basidiomycetes exhibit a direct antiviral effect on herpes simplex virus types I and II, human immunodeficiency virus (HIV), hepatitis B virus, vesicular stomatitis virus, influenza virus, Epstein-Barr virus, and others. Moreover, metabolites of basidiomycetes increased antiviral immunity.
Efremenkova O.V.,RAS Gause Institute of New Antibiotics
Russian Journal of Bioorganic Chemistry | Year: 2016
A-factor, or (2S, 3R)-2-isocapryloyl-3-hydroxymethyl-γ-butirolactone, has been described by A.S. Khokhlov with coworkers and is one of the first studied autoregulators in prokaryotes. A-Factor structure has been confirmed by synthesis. It has been established that actinobacteria produce many substances with structural features closely related to the A-factor, regulating the development of Streptomyces griseus; particularly, they contain γ-bytirolactone, a hydroxymethyl group at position 2, and a fatty acid residue at position 3. These autoregulators are closely related not only in terms of their structure, but also their function, that is, regulation of processes of morphological differentiation, spore formation, and biosynthesis of secondary metabolites, including various antibiotics. This provides grounds for calling them A-factor-like regulators, or gamma-butyrolactones (GBLs), as they are often abbreviated. Structures of 21 natural autoregulators of the group isolated from representatives of eight streptomyces species have been established. Reference strains were used to demonstrate that A-factor regulators are typical of many species of the Actinomycetales order and are specific for these bacteria. They have been described in many species of Streptomyces,Actinomyces, Nocardia, Amycolatopsis, and Micromonospora. Autoregulators exhibit cross-effects with respect to reference strains of various species producing them. Presumably, biosynthesis of A-factor regulators is performed according to a common mechanism starting from fatty acid residues and glycerol as initial metabolites and involving iso-beta-ketoacid; the latter one is cyclized using a molecule of oxidized glycerol forming a nonsaturated gamma-lactone through decondensation at position 2 of oxidized glycerol, which is followed by reduction to A-factor. The first stage of biosynthesis is, supposedly, performed by the product of afsA gene; AfsA is the key enzyme in A-factor biosynthesis. AfsA protein homologues have been found in various streptomyces species. Molecular and genetics studies of A-factor-like autoregulators of S. griseus and some other streptomyces species allowed deciphering a regulatory cascade resulting in morphological differentiation and biosynthesis of secondary metabolites under the effect of nanomolar concentrations of the autoregulators. The action of the A-factor starts with its binding to the A-factor receptor protein (ArpA), which represses the promotor of the target gene. ArpA comprises two domains: N-terminal DNA-binding domain and the A-factor-binding C-terminal domain. ArpA protein binds to the adp4 gene, but DNA is depressed upon A-factor–ArpaA complex formation. This results in transcription of adpA gene encoding a transcription activator AdpA, the central regulator of A-factor regulatory cascade. AdpA amplifies the signal of A-factor, acting as a pleiotropic activator of transcription of at least 72 genes, particularly, the spore formation genes and genes of streptomycin biosynthesis in S. griseus. Altogether, genes activated by AdpA protein form the AdpA regulon. The AdpA-binding consensus DNA sequence has been established. According to their structure, the proteins can be grouped into a larger subfamily of the AraC/XylS family. Study of A-factor-like regulators is of topical interest for both theoretical and practical needs of antibiotic production development. © 2016, Pleiades Publishing, Ltd.
Cogoi S.,University of Udine |
Zorzet S.,University of Trieste |
Shchekotikhin A.E.,RAS Gause Institute of New Antibiotics |
Xodo L.E.,University of Udine
Journal of Medicinal Chemistry | Year: 2015
We previously found that two neighboring G-quadruplexes behave as a molecular switch controlling the expression of HRAS (Cogoi, S.; Schekotikhin, A. E.; Xodo, L. E. Nucl. Acids Res. 2014, DOI: 10.1093/nar/gku574). In this study we have designed anthrathiophenediones with two chloroacetamidine-containing side chains (CATDs) as G-quadruplex binders and have examined their anticancer activity in T24 bladder cancer cells bearing mutant HRAS and in T24 xenografts. The designed CATDs (3a-e), bearing alkyl side chains of different length, penetrate T24 cancer cells more than their analogues with guanidine-containing side chains. The lead compounds 3a and 3c inhibit HRAS expression, metabolic activity, and colony formation in T24 cancer cells. They also activate a strong apoptotic response, as indicated by PARP-1, caspases 3/7, and annexin V/propidium iodide assays. Apoptosis occurs under conditions where cyclin D1 is down-regulated and the cell cycle arrested in G2 phase. Finally, compound 3a inhibits the growth of T24 xenografts and increases the median survival time of nude mice. © 2015 American Chemical Society.