Previously we demonstrated that disruption of ribose-5-phosphate biosynthesis in the pentose phosphate pathway increases the sensitivity of E. coli bacteria to a broad spectrum of antibiotics, and this sensitivity can be suppressed by deletion of the deoB gene. In this study, we demonstrated that antibiotic sensitivity can also be suppressed by disruption of the apt gene, which, along with the deoDB genes, constitutes the salvage pathway for purine base uptake. We suggest that in the rpiAB mutant, these genes, together with the prs gene encoding PRPP synthesis, create a futile cycle, which convers ATP to AMP and PPi. Inactivation each of these genes leads to suppression of the antibiotic sensitivity phenotype of the rpiAB mutant and to restoration of energy status.

In Escherichia coli, ribose-5-phosphate (R5P) biosynthesis occurs via two distinct pathways: an oxidative branch of the pentose phosphate pathway (PPP) originating from glucose-6-phosphate, and a reversed non-oxidative branch originating from fructose-6-phosphate, which relies on transaldolases TalA and TalB. Remarkably, we found that disrupting the oxidative PPP branch by deleting the zwf gene significantly increased bacterial susceptibility to killing by a variety of antibiotics. Surprisingly, additional mutations in the talA and talB genes further enhanced bacterial sensitivity to oxidative stress and antibiotic-mediated killing though they had little impact on the minimal inhibitory concentrations (MICs). The hypersensitivity observed in the zwf talAB mutant could be fully reversed by the processes that either utilize R5P or limited its accumulation. Specifically, activating the purine biosynthetic regulon or inhibiting nucleoside catabolism via deoB gene inactivation, which blocks the conversion of ribose-1-phosphate to R5P, restored bacterial tolerance. Furthermore, enhancing the biosynthesis of cell wall component ADP-heptose from sedoheptulose-7-phosphate suppressed antibiotic killing of the zwf talAB mutant. Biochemical analysis confirmed a direct link between elevated intracellular R5P levels and increased bacterial susceptibility to antibiotics-induced killing. These findings suggest that targeting the PPP could be a promising strategy for developing new therapeutic approaches aimed at potentiating clinically relevant antibiotics.IMPORTANCERecent studies have revealed the crucial role of bacterial cell's metabolic status in its susceptibility to the lethal action of antibacterial drugs. However, there is still no clear understanding of which key metabolic nodes are optimal targets to improve the effectiveness of bacterial infection treatment. Our study establishes that the disruption of the canonical pentose phosphate pathway induces one-way anabolic synthesis of pentose phosphates (aPPP) in E. coli cells, increasing the killing efficiency of various antibiotics. It is also demonstrated that the activation of ribose-5-phosphate utilization processes restores bacterial tolerance to antibiotics. We consider the synthesis of ribose-5-phosphate to be one of the determining factors of bacterial cell stress resistance. Understanding bacterial metabolic pathways, particularly the aPPP's role in antibiotic sensitivity, offers insights for developing novel adjuvant therapeutic strategies to enhance antibiotic potency.

Biosynthesis of ribose-5-phosphate (R5P) underlies all biosynthetic processes associated with biomass growth. Actively dividing cells continuously require building blocks for genome replication, synthesis of ribosomes and other derivatives containing R5P as a carbohydrate backbone. The main source of R5P in the cell is the pentose phosphate pathway (PPP), which is an anabolic sensor designed to coordinate the level of pentose phosphates and reduced NADPH required for anabolic processes. This review is devoted to a comparative analysis of R5P biosynthesis pathways among different domains of microorganisms, the features of PPP regulation in bacterial cells depending on physiological conditions, as well as genetic modifications of PPP and their effect on cell viability. We emphasize that ribose metabolism is a factor in the consolidation of cellular homeostasis under conditions of intensive biomass growth and the discrepancy between the processes of ribose synthesis and consumption is marked by spontaneous cell death.

The effect of copper doping of ZnSe:Fe crystals on the kinetics of luminescence of iron ions is investigated in this work. It has been discovered that doping with copper leads to a sharp decrease in the radiative recombination of iron ions at a temperature of 77 K. The obtained results are explained based on the model of nonradiative relaxation of iron ions due to Auger recombination with the participation of electrons in the conduction band.

Abstract—Solving the problem of multidrug resistance currently requires the development of nonstandard approaches, since the potential for creating new antibiotics is almost exhausted. Controlling the metabolism of a pathogen in order to increase its susceptibility to antibacterial therapy is considered the most promising area of research for the creation of new combination drugs. In recent years, the number of studies devoted to investigation the role of the biosynthesis of the cell wall component ADP-heptose in the sensitivity of bacteria to antibiotics, as well as in the pathogenesis of bacterial infection, has increased. This review examines the main directions of scientific research in the field of use of ADP-heptose and its analogues in the treatment of bacterial infections. The exclusive role of ADP-heptose in the induction of an immune response is known through the activation of the NF-κB signaling pathway and the synthesis of pro-inflammatory cytokines. Our latest work has shown that disruption of the synthesis of ADP-heptose and the efflux of sedoheptulose-7-phosphate from the pentose phosphate pathway induces a redox imbalance and completely disorganizes the metabolism of low molecular weight thiols such as hydrogen sulfide, cysteine, and glutathione, which makes the bacterial cell extremely vulnerable to the action of antibiotics. We demonstrate that the hypersensitivity of ADP-heptose mutants to a wide range of antibiotics is explained by a new metabolic status rather than by changes in cell wall permeability. Thus, potential inhibitors of ADP-heptose biosynthesis can combine several positive qualities: an immunomodulatory effect and a powerful potentiating effect in combination with antibiotic therapy.

Disruption of both branches of the canonical pentose phosphate pathway (PPP) in E. coli by combined inactivation of the zwf and talAB genes provokes the restoration of the ancient anabolic variant of PPP (aPPP). In the aPPP, pentose-5-phosphates are synthesized unidirectionally from fructose-6-phosphate and glyceraldehyde-3-phosphate by transketolase B, aldolase A, and phosphatase GlpX, converting sedoheptulose-1,7-bisphosphate to sedoheptulose-7-phosphate. Unexpectedly, the double zwf talAB mutant exhibits decreased survival after treatment by diverse classes of antibiotics with little effect on the minimal inhibitory concentration. Simultaneously, we found that killing effect of antimicrobials on the zwf talAB mutant could be reversed by the inactivation of either purR or deoB genes, both responsible for ribose-5-phosphate content in the mutant strain. Enhanced biosynthesis of the cell wall component ADP-heptose from sedoheptulose-7-phosphate also suppressed killing effect of antibiotics on the zwf talAB mutant. Furthermore, the inactivation of the Entner-Doudoroff pathway ( Δedd ) or shifting the metabolic equilibrium by the addition of exogenous phosphogluconate reverts aPPP to glycolysis, preventing the accumulation of excess pentose phosphates and the occurrence of the futile cycle in zwf talAB cells, thus desensitizing them to antibiotics. Our findings show that ribose-5-phosphate metabolism plays a crucial role in bacterial tolerance to a wide range of bactericidal antibiotics. We propose that targeting PPP could be a promising strategy for developing new therapeutic agents aimed at potentiating clinically significant antimicrobials. IMPORTANCE Recent studies have revealed the crucial role of bacterial cell’s metabolic status in its susceptibility to the lethal action of antibacterial drugs. However, there is still no clear understanding of which key metabolic nodes are optimal targets to improve the effectiveness of bacterial infection treatment. Our study establishes that the disruption of the canonical pentose phosphate pathway induces one-way anabolic synthesis of pentose phosphates (aPPP) in E. coli cells, significantly increasing the killing efficiency of various antibiotics. It is also demonstrated that the activation of ribose-5-phosphate utilization processes restores bacterial tolerance to antibiotics. We consider the synthesis of ribose-5-phosphate to be one of the determining factors of bacterial cell stress resistance. Understanding bacterial metabolic pathways, particularly the aPPP’s role in antibiotic sensitivity, offers insights for developing novel adjuvant therapeutic strategies to enhance antibiotic potency. ### Competing Interest Statement The authors have declared no competing interest.

Considering an anisotropic cosmological background is an interesting and simultaneously challenging problem of theoretical physics, since we not only assume a high degree of anisotropy in the early stages of the Universe, but also observe it to a small degree until now. In this paper we have constructed the unconstrained action for the perturbations above Bianchi I type background in the most general scalar-tensor theory of gravity, the Horndeski theory, and evaluate the effect of the deviation from the anisotropic background on the previously established stable solution obtained in previous works.

In Escherichia coli cells, the main enzymes involved in pentose interconversion are ribose-5-phosphate isomerases RpiA and RpiB and ribulose-5-phosphate epimerase Rpe. The inactivation of rpiAB limits ribose-5-phosphate (R5P) synthesis via the oxidative branch of the pentose phosphate pathway (PPP) and unexpectedly results in antibiotic supersensitivity. This type of metabolism is accompanied by significant changes in the level of reducing equivalents of NADPH and glutathione, as well as a sharp drop in the ATP pool. However, this redox and energy imbalance does not lead to the activation of the soxRS oxidative stress defense system but the increased sensitivity to oxidants paraquat and H2O2. The deletion of rpiAB leads to a significant increase in the activity of transketalase (Tkt), a key enzyme of the nonoxidative branch of the PPP and increased sensitivity to ribose added in the growth medium. The phenotype of supersensitivity of rpiAB to antibiotics and ribose can be suppressed by activating the utilization of sedoheptulose-7-phosphate, which originates from R5P, to LPS synthesis or limitation of nucleoside catabolism by the inactivation of the DeoB enzyme, responsible for conversion of ribose-1-phospate to R5P. Our results indicate that the induction of unidirectional synthesis of R5P is the cause of supersensitivity to antibiotics in rpiAB mutant.

Using two-photon confocal microscopy in the spectral range of 0.44–0.73 μm, the spatial distribution of the luminescent characteristics of CVD-ZnSe doped with chromium using the HIP process was studied. It has been established that as a result of this process, four types of impurity-defect centers are formed in the crystal. It is shown that their formation involves point centers that form in the doping zone and diffuse deep into the crystal. Assumptions are made about the nature of these point centers.

The time dependence of the luminescence power of the Fe2+ ion in ZnSe at liquid nitrogen temperature has been investigated where it is excited by a short laser pulse with a wavelength of 2940 nm at various concentrations of Fe2+ ions and various pulse energy density on the sample surface. The shape of the luminescence decay curve is shown to depend both on the Fe2+ concentration and on the laser pulse energy density. This behavior of luminescence kinetics was interpreted as a manifestation of concentration quenching of the Fe2+ excited state. A theoretical description of the observed dependences is proposed, the best agreement between calculated and experimental curves being obtained if we assume that the probability of quenching per time unit is proportional to the square of the concentration of Fe2+ ions in the excited state.

Abstract—Low molecular-weight thiols as glutathione and cysteine are an important part of the cell’s redox regulation system. Previously, we have shown that inactivation of ADP-heptose synthesis in Escherichia coli with a gmhA deletion induces the oxidative stress. It is accompanied by rearrangement of thiol homeostasis and increased sensitivity to antibiotics. In our study, we found that restriction of cysteine metabolism (∆cysB and ∆cysE) and inhibition of glutathione synthesis (∆gshAB) lead to a decrease in the sensitivity of the ∆gmhA mutant to antibiotics but not to its expected increase. At the same time, blocking of the export of cysteine (∆eamA) or increasing import (Ptet-tcyP) into cells of the oxidized form of cysteine–cystine leads to an even greater increase in the sensitivity of gmhA-deleted cells to antibiotics. In addition, there is no correlation between the cytotoxic effect of antibiotics and the level of reactive oxygen species (ROS), the total pool of thiols, or the viability of the initial cell population. However, a correlation between the sensitivity to antibiotics and the level of oxidized glutathione in cells was found in our study. Apparently, a decrease in the content of low-molecular-weight thiols saves NADPH equivalents and limits the processes of protein redox modification. This leads to increasing of resistance of the ∆gmhA strain to antibiotics. An increase in low-molecular-weight thiols levels requires a greater expenditure of cell resources, leads to an increase in oxidized glutathione and induces to greater increase in sensitivity of the ∆gmhA strain to antibiotics.

основная цель – развитие системного подхода в рамках структурного анализа и математического моделирования для решения задач, связанных с обеспечением безопасности и эффективности работы технических систем, подлежащие расчету с помощью механических колебательных структур с сосредоточенными параметрами. Под структурным подходом понимается методология решения задач, основанная на сопоставлении колебательным структурам схем динамически эквивалентных систем автоматического управления. Подход предполагает разбиение объекта на составляющие элементы и определение связей. Элементами системы являются твердые тела и пружины. Рассматриваются системы, обладающие линейными свойствами. В качестве внешних возмущающих факторов выступают связные силовые колебания. Оценка состояния системы производится на основе податливости, изменяющейся в зависимости от частоты силового воздействия. Показано, что в механических колебательных системах множество обобщенных динамических состояний, связанных с характеристиками внешних сил и с координатами точек, определяющих динамическое соответствие, может быть выражено в виде карты динамических инвариантов. Одним из ключевых результатов работы является то, что задача оценки, контроля и формирования динамических состояний системы может быть проведена с помощью декомпозиции полной совокупности состояний на конечное число классов динамических состояний, обладающих фиксированными динамическими инвариантами, что позволяет реализовать системный подход к оценке системы с учетом нескольким параметров the work is aimed at developing a systemic approach within the framework of the methodology of structural mathematical modeling to solve problems related to ensuring the safety and efficiency of technical objects, whose calculation schemes can be represented by mechanical oscillatory systems with concentrated parameters. The structural approach involves solving problems based on the comparison of mechanical oscillatory systems with structural diagrams of equivalent automatic control systems in dynamic terms. The approach involves breaking down the object into component parts and determining their connections. The elements of the system are solid bodies and springs, while connected force oscillations act as external disturbing factors. The evaluation of the system's state is based on dynamic compliance, which depends on the frequency of external disturbances. It is shown that in mechanical oscillatory systems, the set of generalized dynamic states, which depend on the coefficients of connection of external force disturbances and the coordinates of points determining dynamic correspondence, can be expressed in the form of a map of dynamic invariants. One of the key results of the work is that the task of evaluating, controlling, and forming the dynamic states of the system can be carried out by decomposing the full set of states into a finite number of classes of dynamic states that have fixed dynamic invariants. This allows for a systemic approach to evaluating the system taking into account multiple parameters

The pathogenesis of Alzheimer's disease (AD) is associated with the formation of cerebral amyloid plaques, the main components of which are the modified Aβ molecules as well as the metal ions. Aβ isomerized at Asp7 residue (isoD7-Aβ) is the most abundant isoform in amyloid plaques. We hypothesized that the pathogenic effect of isoD7-Aβ is due to the formation of zinc-dependent oligomers, and that this interaction can be disrupted by the rationally designed tetrapeptide (HAEE). Here, we utilized surface plasmon resonance, nuclear magnetic resonance, and molecular dynamics simulation to demonstrate Zn2+-dependent oligomerization of isoD7-Aβ and the formation of a stable isoD7-Aβ:Zn2+:HAEE complex incapable of forming oligomers. To demonstrate the physiological importance of zinc-dependent isoD7-Aβ oligomerization and the ability of HAEE to interfere with this process at the organismal level, we employed transgenic nematodes overexpressing human Aβ. We show that the presence of isoD7-Aβ in the medium triggers extensive amyloidosis that occurs in a Zn2+-dependent manner, enhances paralysis, and shortens the animals' lifespan. Exogenous HAEE completely reverses these pathological effects of isoD7-Aβ. We conclude that the synergistic action of isoD7-Aβ and Zn2+ promotes Aβ aggregation and that the selected small molecules capable of interrupting this process, such as HAEE, can potentially serve as anti-amyloid therapeutics.

Inactivation of enzymes responsible for biosynthesis of the cell wall component of ADP-glycero-manno-heptose causes the development of oxidative stress and sensitivity of bacteria to antibiotics of a hydrophobic nature. The metabolic precursor of ADP-heptose is sedoheptulose-7-phosphate (S7P), an intermediate of the non-oxidative branch of the pentose phosphate pathway (PPP), in which ribose-5-phosphate and NADPH are generated. Inactivation of the first stage of ADP-heptose synthesis (ΔgmhA) prevents the outflow of S7P from the PPP, and this mutant is characterized by a reduced biosynthesis of NADPH and of the Glu-Cys-Gly tripeptide, glutathione, molecules known to be involved in the resistance to oxidative stress. We found that the derepression of purine biosynthesis (∆purR) normalizes the metabolic equilibrium in PPP in ΔgmhA mutants, suppressing the negative effects of gmhA mutation likely via the over-expression of the glycine–serine pathway that is under the negative control of PurR and might be responsible for the enhanced synthesis of NADPH and glutathione. Consistently, the activity of the soxRS system, as well as the level of glutathionylation and oxidation of proteins, indicative of oxidative stress, were reduced in the double ΔgmhAΔpurR mutant compared to the ΔgmhA mutant.

Hyaluronic acid finds expanding application in the pharmaceutical and cosmetic industries, resulting in an increasing need for the high-quality substance. The main production processes to obtain hyaluronic acid in commercial quantities are extraction from animal tissues and bacterial fermentation using opportunistic Streptococcus strains. The production by recombinant bacteria that are safe for humans seems to be an efficient and economically viable way to obtain hyaluronic acid. The recombinant producer strains constructed on the basis of the Bacillus subtilis platform make it possible to obtain the yield and quality of the product comparable to those of commercially developed Streptococcus strains. By varying genetic, biochemical, and biotechnological factors, it becomes possible to obtain products with different target molecular weights. Despite the results achieved, the potential of the B. subtilis platform for the construction of recombinant hyaluronic acid producer strains has not been exhausted.

An approach to the formation of a methodological basis for the system analysis of the dynamics of mechanical oscillatory structures based on frequency functions and damping functions is being developed. The argument of the functions is the coefficient of connectivity of the forms of motion of mass-inertia elements. The connectivity coefficient reflects the lever relationship of the parameters of the generalized coordinates. Mechanical oscillatory systems that are not connected to the support surfaces are considered. Mechanical oscillatory systems are formed by two mass-inertia elements, a spring and a damper. The aim of the study is to develop a method for constructing frequency functions and damping functions. The method is based on the use of an energy ratio that relates the kinetic, potential energy and the values of the energy dissipation function. The Lagrange formalism is used for composing differential equations. To determine the forms of frequency functions and damping functions, the so-called parametrizing function is used. Frequency functions and damping functions for mechanical oscillatory systems performing free movements are constructed. The graph-analytic evaluation of the extreme properties of frequency functions and damping functions is carried out. The possibility of the existence of four extreme values for frequency functions is shown. A topological criterion for classifying the forms of graphs of frequency functions and damping functions is proposed. The developed method can be used to display the dynamic features of mechanical oscillatory systems that include devices for converting movements.

Counteraction of the origin and distribution of multidrug-resistant pathogens responsible for intra-hospital infections is a worldwide issue in medicine. In this brief review, we discuss the results of our recent investigations, which argue that many antibiotics, along with inactivation of their traditional biochemical targets, can induce oxidative stress (ROS production), thus resulting in increased bactericidal efficiency. As we previously showed, hydrogen sulfide, which is produced in the cells of different pathogens protects them not only against oxidative stress but also against bactericidal antibiotics. Next, we clarified the interplay of oxidative stress, cysteine metabolism, and hydrogen sulfide production. Finally, demonstrated that small molecules, which inhibit a bacterial enzyme involved in hydrogen sulfide production, potentiate bactericidal antibiotics including quinolones, beta-lactams, and aminoglycosides against bacterial pathogens in in vitro and in mouse models of infection. These inhibitors also suppress bacterial tolerance to antibiotics by disrupting the biofilm formation and substantially reducing the number of persister bacteria, which survive the antibiotic treatment. We hypothesise that agents which limit hydrogen sulfide biosynthesis are effective tools to counteract the origin and distribution of multidrug-resistant pathogens.