Современные подходы к разработке специфической терапии особо опасных токсикоинфекций

Category A select agents continue to be major threat to human population both as naturally occurring diseases and as potential weapon of bioterrorists. Anthrax and botulism are probably the most threatening agents as both have virtually uncontrolled natural reservoirs from which they can be isolated and propagated. Available specific antitoxin therapy of both diseases is outdated; its efficiency is questionable as well as safety of reactogenic or human-derived components used in treatment. Highly sensitive toxin detection techniques are still not as widespread as it needed for timely alerting medical services. There is urgent need of pre-exposure prophylaxis and postexposure specific antitoxin therapy for anthrax and botulism. Analysis of modern studies in the field suggests oligoclonal antibodies acting against receptor-binding toxin subunits and nucleic acid aptamers as allosteric inhibitors of metlloproteolytic toxin components as the most promising candidates for development of efficient antitoxin therapyОсобо опасные токсикоинфекции являются значительной угрозой здоровью населения и нерешенной проблемой обеспечения биологической безопасности. Наибольшую опасность представляют собой ботулизм и сибирская язва, которые не только имеют практически не контролируемые природные резервуары, но также могут служить возможным оружием биотеррористов. Специфическая терапия этих заболеваний практически отсутствует, существующие методы имеют ограниченные возможности применения и низкую эффективность, в то время как высокочувствительная ранняя диагностика еще не получила широкого распространения. Необходима срочная разработка средств специфической терапии и экстренной профилактики ботулизма и сибирской язвы. Анализ современных тенденций развития этих направлений показал, что на данный момент, вероятно, наиболее перспективными технологиями для создания антитоксинов являются олигоклональные антитела и аптамеры, аллостерически ингибирующие активность эффекторных компонентов обоих токсинов — цинкзависимых протеаз

Аптамеры для терапии бактериальных инфекций: проблемы и перспективы

Aptamers are short single-stranded oligonucleotides which are selected via targeted chemical evolution in vitro to bind a molecular target of interest. The aptamer selection technology is designated as SELEX (Systematic evolution of ligands by exponential enrichment). SELEX enables isolation of oligonucleotide aptamers binding a wide range of targets of interest with little respect for their nature and molecular weight. A number of applications of aptamer selection were developed ranging from biosensor technologies to antitumor drug discovery. First aptamer-based pharmaceutical (Macugen) was approved by FDA for clinical use in 2004, and since then more than ten aptamer-based drugs undergo various phases of clinical trials. From the medicinal chemist’s point of view, aptamers represent a new class of molecules suitable for the development of new therapeutics. Due to the stability, relative synthesis simplicity, and development of advanced strategies of target specific molecular selection, aptamers attract increased attention of drug discovery community. Difficulties of the development of next-generation antibiotics basing on the conventional basis of combinatorial chemistry and high-throughput screening have also amplified the interest to aptamer-based therapeutic candidates. The present article reviews the investigations focused on the development of antibacterial aptamers and discusses the potential and current limitations of the use of this type of therapeutic molecules.Аптамеры ― короткие одноцепочечные фрагменты нуклеиновых кислот, которые в процессе направленной химической «эволюции в пробирке» на основе технологии SELEX отбирают на специфичность к избранной молекулярной мишени. Возможность получать при помощи SELEX олигонуклеотиды, связывающие широчайший спектр высоко- и низкомолекулярных лигандов, а также простота автоматизированного синтеза привели к созданию широкого спектра приложений аптамеров ― от биосенсоров до противоопухолевых препаратов. С точки зрения медицинской химии, аптамеры являются новым классом молекул, на основе которых могут быть разработаны лекарственные препараты. Поэтому, а также ввиду стабильности, относительной простоты синтеза и создания все более эффективных стратегий селекции мишеньспецифических молекул аптамеры привлекают внимание разработчиков лекарственных средств, в том числе и антибактериальных. Интерес к антибактериальным аптамерам усиливается и в связи с проблемами, возникшими при разработке принципиально новых антибактериальных средств на основе классических химических соединений ― как малых органических молекул, так и синтетических модификаций известных антибиотиков. В настоящем обзоре рассматриваются работы, направленные на создание противоинфекционных аптамеров, и обсуждаются как потенциал, так и существующие на данном этапе ограничения, свойственные этому классу терапевтических молекул

Study of the process e+e−→3(π+π−) in the c.m. energy range 1.5–2.0 GeV with the CMD-3 detector

AbstractThe cross section of the process e+e−→3(π+π−) has been measured using a data sample of 22 pb−1 collected with the CMD-3 detector at the VEPP-2000 e+e− collider. 7956 signal events are selected in the center-of-mass energy range 1.5–2.0 GeV. The measured cross section exhibits a sharp drop near the pp¯ threshold. A first study of dynamics of six-pion production has been performed

The use of 4-Hexylresorcinol as antibiotic adjuvant

Ever decreasing efficiency of antibiotic treatment due to growing antibiotic resistance of pathogenic bacteria is a critical issue in clinical practice. The two generally accepted major approaches to this problem are the search for new antibiotics and the development of antibiotic adjuvants to enhance the antimicrobial activity of known compounds. It was therefore the aim of the present study to test whether alkylresorcinols, a class of phenolic lipids, can be used as adjuvants to potentiate the effect of various classes of antibiotics. Alkylresorcinols were combined with 12 clinically used antibiotics. Growth-inhibiting activity against a broad range of pro- and eukaryotic microorganisms was determined. Test organisms did comprise 10 bacterial and 2 fungal collection strains, including E. coli and S. aureus, and clinical isolates of K. pneumoniae. The highest adjuvant activity was observed in the case of 4-hexylresorcinol (4-HR), a natural compound found in plants with antimicrobial activity. 50% of the minimal inhibitory concentration (MIC) of 4-HR caused an up to 50-fold decrease in the MIC of antibiotics of various classes. Application of 4-HR as an adjuvant revealed its efficiency against germination of bacterial dormant forms (spores) and prevented formation of antibiotic-tolerant persister cells. Using an in vivo mouse model of K. pneumoniae-induced sepsis, we could demonstrate that the combination of 4-HR and polymyxin was highly effective. 75% of animals were free of infection after treatment as compared to none of the animals receiving the antibiotic alone. We conclude that alkylresorcinols such as 4-HR can be used as an adjuvant to increase the efficiency of several known antibiotics. We suggest that by this approach the risk for development of genetically determined antibiotic resistance can be minimized due to the multimodal mode of action of 4-HR. © 2020 Nikolaev et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Results from the

Two e+e− colliders, VEPP-4M and VEPP2000, are taking data at the Budker INP in Novosibirsk, Russia. KEDR detector at the VEPP-4M collider continues deliver precision measurements of the charmonium family. Results of the ψ(2S ) and ψ(3770) study are presented. Two energy scans of a center-of-mass energy range from 1 GeV to 2 GeV has been performed by the VEPP2000 collider with an integrated luminosity of about 35 pb−1, collected by each of the CMD-3 and SND detectors. This paper reports the latest results from VEPP-2000 obtained by the CMD-3 collaboration