RAS Gause Institute of New Antibiotics

Moscow, Russia

RAS Gause Institute of New Antibiotics

Moscow, Russia

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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.


Printsevskaya S.S.,RAS Gause Institute of New Antibiotics | Reznikova M.I.,RAS Gause Institute of New Antibiotics | Korolev A.M.,RAS Gause Institute of New Antibiotics | Lapa G.B.,RAS Gause Institute of New Antibiotics | And 4 more authors.
Future Medicinal Chemistry | Year: 2013

Background: The ability of boron-containing compounds to undergo a number of novel binding interactions with drug target functional groups has recently been described. In an extension of this work, we have incorporated a boron-containing scaffold, the benzoxaborole, into several glycopeptides antibiotics. The aim of this work is to exploit the inherent reactivity of boron to gain additional interactions with the bacterial cell wall components to improve binding affinity and to thereby overcome resistance. Results: Three antibacterial glycopeptides (vancomycin, eremomycin and teicoplanin aglycone) have been selected for the construction of a series of 12 new benzoxaborole-glycopeptide conjugates. The hybrid antibiotics, in which the benzoxaborole and glycopeptide moieties were separated by a linker, exhibited excellent antibacterial activity against Gram-positive bacteria, including those with intermediate susceptibility to glycopeptides. Some analogs also demonstrated activity against vancomycin-resistant enterococci. Conclusion: Conjugation of antibiotics with benzoxaborole derivatives provides antibiotics with new and useful properties. Teicoplanin aglycone-benzoxaborole derivatives overcome resistance of Gram-positive bacteria to vancomycin. © 2013 Future Science Ltd.


Fomich M.A.,National Academy of Sciences of Belarus | Kvach M.V.,National Academy of Sciences of Belarus | Navakouski M.J.,Primetech ALC | Weise C.,Free University of Berlin | And 3 more authors.
Organic Letters | Year: 2014

Azide and phosphoramidite functions were found to be compatible within one molecule and stable for months in solution kept frozen at -20 °C. An azide-carrying phosphoramidite was used for direct introduction of multiple azide modifications into synthetic oligonucleotides. A series of azide-containing oligonucleotides were modified further using click reactions with alkynes. © 2014 American Chemical Society.


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


Strukova E.N.,RAS Gause Institute of New Antibiotics | Portnoy Y.A.,RAS Gause Institute of New Antibiotics | Zinner S.H.,Harvard University | Firsov A.A.,RAS Gause Institute of New Antibiotics
Journal of Antimicrobial Chemotherapy | Year: 2016

Objectives: To examine the predictive power of the ratios of the 24 h AUC (AUC24) to the mutant prevention concentration (MPC) and the MIC, the selection of ciprofloxacin-resistant mutants of Pseudomonas aeruginosa was studied in an in vitro dynamic model. Methods: Four clinical isolates of P. aeruginosa with MPC/MIC ratios from 5.6 to 32 were exposed to twice-daily ciprofloxacin for 3 days over a 100- to 200-fold range of the AUC24/MIC ratio. Results: The emergence of P. aeruginosa resistance to ciprofloxacin was concentration dependent: mutants resistant to 2-16 × MIC were enriched at antibiotic concentrations between the MIC and MPC, but not at concentrations below the MIC or above the MPC. Both AUC24/MIC and AUC24/MPC relationships with the area under the bacterial mutant concentration-time curve (AUBCM) were bell-shaped. These relationships predict highly variable 'anti-mutant' AUC24/MIC and AUC24/MPC ratios: e.g. with mutants resistant to 2 × MIC the ratios ranged from 220 to 1100 and from 7 to 180 h, respectively. Using combined data for the four studied organisms, correlations between AUBCM and AUC24/MIC or AUC24/MPC were established (r2 = 0.75 and 0.65, respectively). Much stronger correlation was observed between AUC24/MIC and the area between the cut-off level at 108 cfu/mL and the time-kill curve (ABBC) as an integral index of the antimicrobial effect of ciprofloxacin on the parental strains (r2 = 0.93). Conclusions: Findings obtained with ciprofloxacin-exposed P. aeruginosa are consistent with the mutant selection window hypothesis. AUC24/MIC and AUC24/MPC relationships with resistance were more bacterial strain specific than AUC24/MIC relationships with fluoroquinolone-induced killing of susceptible cells. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.


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.

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