Discovery of aminopiperidine based potent & novel topoisomerase inhibitor with broad spectrum anti-bacterial activity.

Bacterial DNA gyrase and topoisomerase IV inhibition has emerged as a promising strategy for the cure of infections caused by antibiotic-resistant bacteria. The Novel Bacterial Topoisomerase Inhibitors (NBTIs) bind to a different site from that of the quinolones with novel mechanism of action. This evades the existing target-mediated bacterial resistance associated with quinolones. This article presents our efforts to identify in vitro potent and broad-spectrum antibacterial agent 4l.

Research on the Coupling Effect of NBTI and TID for FDSOI pMOSFETs.

The coupling effect of negative bias temperature instability (NBTI) and total ionizing dose (TID) was investigated by simulation based on the fully depleted silicon on insulator (FDSOI) PMOS. After simulating the situation of irradiation after NBT stress, it was found that the NBTI effect weakens the threshold degradation of FDSOI PMOS under irradiation. Afterward, NBT stress was decomposed into high gate voltage stress and high-temperature stress, which was applied to the device simultaneously with irradiation. The devices under high gate voltage exhibited more severe threshold voltage degradation after irradiation compared to those under low gate voltage. Devices at high temperatures also exhibit more severe threshold degradation after irradiation compared to devices under low temperatures. Finally, the simultaneous effect of high gate voltage, high temperature, and irradiation on the device was investigated, which fully demonstrated the impact of the NBT stress on the TID effect, resulting in far more severe threshold voltage degradation.

A Reliability Investigation of VDMOS Transistors: Performance and Degradation Caused by Bias Temperature Stress.

This study aimed to comprehensively understand the performance and degradation of both p- and n-channel vertical double diffused MOS (VDMOS) transistors under bias temperature stress. Conducted experimental investigations involved various stress conditions and annealing processes to analyze the impacts of BT stress on the formation of oxide trapped charge and interface traps, leading to threshold voltage shifts. Findings revealed meaningful threshold voltage shifts in both PMOS and NMOS devices due to stresses, and the subsequent annealing process was analyzed in detail. The study also examined the influence of stress history on self-heating behavior under real operating conditions. Additionally, the study elucidated the complex correlation between stress-induced degradation and device reliability. The insights contribute to optimizing the performance and permanence of VDMOS transistors in practical applications, advancing semiconductor technology. This study underscored the importance of considering stress-induced effects on device reliability and performance in the design and application of VDMOS transistors.

Interaction of Negative Bias Instability and Self-Heating Effect on Threshold Voltage and SRAM (Static Random-Access Memory) Stability of Nanosheet Field-Effect Transistors.

In this paper, we investigate the effects of negative bias instability (NBTI) and self-heating effect (SHE) on threshold voltage in NSFETs. To explore accurately the interaction between SHE and NBTI, we established an NBTI simulation framework based on trap microdynamics and considered the influence of the self-heating effect. The results show that NBTI weakens the SHE effect, while SHE exacerbates the NBTI effect. Since the width of the nanosheet in NSFET has a significant control effect on the electric field distribution, we also studied the effect of the width of the nanosheet on the NBTI and self-heating effect. The results show that increasing the width of the nanosheet will reduce the NBTI effect but will enhance the SHE effect. In addition, we extended our research to the SRAM cell circuit, and the results show that the NBTI effect will reduce the static noise margin (SNM) of the SRAM cell, and the NBTI effect affected by self-heating will make the SNM decrease more significantly. In addition, our research results also indicate that increasing the nanosheet width can help slow down the NBTI effect and the negative impact of NBTI on SRAM performance affected by the self-heating effect.

Interfacial Resistive Switching of Niobium-Titanium Anodic Memristors with Self-Rectifying Capabilities.

A broad compositional range of Nb-Ti anodic memristors with volatile and self-rectifying behaviour was studied using a combinatorial screening approach. A Nb-Ti thin-film combinatorial library was co-deposited by sputtering, serving as the bottom electrode for the memristive devices. The library, with a compositional spread ranging between 22 and 64 at.% Ti was anodically oxidised, the mixed oxide being the active layer in MIM-type structures completed by Pt discreet top electrode patterning. By studying I-U sweeps, memristors with self-rectifying and volatile behaviour were identified. Moreover, all the analysed memristors demonstrated multilevel properties. The best-performing memristors showed HRS/LRS (high resistive state/low resistive state) ratios between 4 and 6 × 105 and very good retention up to 106 successive readings. The anodic memristors grown along the compositional spread showed very good endurance up to 106 switching cycles, excluding those grown from alloys containing between 31 and 39 at.% Ti, which withstood only 10 switching cycles. Taking into consideration all the parameters studied, the Nb-46 at.% Ti composition was screened as the parent metal alloy composition, leading to the best-performing anodic memristor in this alloy system. The results obtained suggest that memristive behaviour is based on an interfacial non-filamentary type of resistive switching, which is consistent with the performed cross-sectional TEM structural and chemical characterisation.

In-situ investigation of the decomposition process in cold-rolled Nb53Ti47 alloy.

The multi-layer composite development primarily aims to develop and test the components of the next generation of hadron colliders (e.g., Large Hadron Collider - LHC) consisting of superconducting raw materials. Multilayer sheet is very similar to the commonly used NbTi wire products, a 2D version of the commercial wire. These composites consist of layers such as NbTi superconductor, Nb diffusion barrier (between NbTi and Cu) and Cu stabilizer. In ß-NbTi superconducting alloys, α-Ti precipitates are primary flux pinning centers that maintain stable superconductivity. A multi-step series of heat treatments and cold-forming processes can develop the flux pinning centers. Practically, this process means three heat treatments of constant period and temperature and drawing or rolling between the heat treatments. The study aimed to describe the behavior of the cold-rolled (ε = 3.35) Nb53Ti47w% alloys during isothermal heating at 673 K as a function of heating time. The processes during the aging were investigated by the in-situ XRD method in the heating chamber. The X-ray diffraction patterns were evaluated by Rietveld refinement. The thermally activated spinodal decomposition and precipitation processes were described based on the phases identified at the individual heat treatment steps and their lattice parameters. The in-situ study also revealed an increase in α-Ti precipitation with time and decomposition that co-occurs. This is the basic study that prepares the applicability of the alloy.

Actions of a Novel Bacterial Topoisomerase Inhibitor against Neisseria gonorrhoeae Gyrase and Topoisomerase IV: Enhancement of Double-Stranded DNA Breaks.

Novel bacterial topoisomerase inhibitors (NBTIs) are an emerging class of antibacterials that target gyrase and topoisomerase IV. A hallmark of NBTIs is their ability to induce gyrase/topoisomerase IV-mediated single-stranded DNA breaks and suppress the generation of double-stranded breaks. However, a previous study reported that some dioxane-linked amide NBTIs induced double-stranded DNA breaks mediated by Staphylococcus aureus gyrase. To further explore the ability of this NBTI subclass to increase double-stranded DNA breaks, we examined the effects of OSUAB-185 on DNA cleavage mediated by Neisseria gonorrhoeae gyrase and topoisomerase IV. OSUAB-185 induced single-stranded and suppressed double-stranded DNA breaks mediated by N. gonorrhoeae gyrase. However, the compound stabilized both single- and double-stranded DNA breaks mediated by topoisomerase IV. The induction of double-stranded breaks does not appear to correlate with the binding of a second OSUAB-185 molecule and extends to fluoroquinolone-resistant N. gonorrhoeae topoisomerase IV, as well as type II enzymes from other bacteria and humans. The double-stranded DNA cleavage activity of OSUAB-185 and other dioxane-linked NBTIs represents a paradigm shift in a hallmark characteristic of NBTIs and suggests that some members of this subclass may have alternative binding motifs in the cleavage complex.

A 2.8 Å Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase.

Since 2000, some thirteen quinolones and fluoroquinolones have been developed and have come to market. The quinolones, one of the most successful classes of antibacterial drugs, stabilize DNA cleavage complexes with DNA gyrase and topoisomerase IV (topo IV), the two bacterial type IIA topoisomerases. The dual targeting of gyrase and topo IV helps decrease the likelihood of resistance developing. Here, we report on a 2.8 Å X-ray crystal structure, which shows that zoliflodacin, a spiropyrimidinetrione antibiotic, binds in the same DNA cleavage site(s) as quinolones, sterically blocking DNA religation. The structure shows that zoliflodacin interacts with highly conserved residues on GyrB (and does not use the quinolone water-metal ion bridge to GyrA), suggesting it may be more difficult for bacteria to develop target mediated resistance. We show that zoliflodacin has an MIC of 4 µg/mL against Acinetobacter baumannii (A. baumannii), an improvement of four-fold over its progenitor QPT-1. The current phase III clinical trial of zoliflodacin for gonorrhea is due to be read out in 2023. Zoliflodacin, together with the unrelated novel bacterial topoisomerase inhibitor gepotidacin, is likely to become the first entirely novel chemical entities approved against Gram-negative bacteria in the 21st century. Zoliflodacin may also become the progenitor of a new safer class of antibacterial drugs against other problematic Gram-negative bacteria.

Targeting novel sites in DNA gyrase for development of anti-microbials.

Antimicrobial resistance in bacteria poses major challenges in selection of the therapeutic regime for managing the infectious disease. There is currently an upsurge in the appearance of multiple drug resistance in bacterial pathogens and a decline in the discovery of novel antibiotics. DNA gyrase is an attractive target used for antibiotic discovery due to its vital role in bacterial DNA replication and segregation in addition to its absence in mammalian organisms. Despite the presence of successful antibiotics targeting this enzyme, there is a need to bypass the resistance against this validated drug target. Hence, drug development in DNA gyrase is a highly active research area. In addition to the conventional binding sites for the novobiocin and fluoroquinolone antibiotics, several novel sites are being exploited for drug discovery. The binding sites for novel bacterial type II topoisomerase inhibitor (NBTI), simocyclinone, YacG, Thiophene and CcdB are structurally and biochemically validated active sites, which inhibit the supercoiling activity of topoisomerases. The novel chemical moieties with varied scaffolds have been identified to target DNA gyrase. Amongst them, the NBTI constitutes the most advanced DNA gyrase inhibitor which are in phase III trial of drug development. The present review aims to classify the novel binding sites other than the conventional novobiocin and quinolone binding pocket to bypass the resistance due to mutations in the DNA gyrase enzyme. These sites can be exploited for the identification of new scaffolds for the development of novel antibacterial compounds.

Evaluation on Temperature-Dependent Transient VT Instability in p-GaN Gate HEMTs under Negative Gate Stress by Fast Sweeping Characterization.

In this work, temperature-dependent transient threshold voltage (VT) instability behaviors in p-GaN/AlGaN/GaN HEMTs, with both Schottky gate (SG) and Ohmic gate (OG), were investigated systematically, under negative gate bias stress, by a fast voltage sweeping method. For SG devices, a concave-shaped VT evolution gradually occurs with the increase in temperature, and the concave peak appears faster with increasing reverse bias stress, followed by a corresponding convex-shaped VT recovery process. In contrast, the concave-shaped VT evolution for OG devices that occurred at room temperature gradually disappears in the opposite shifting direction with the increasing temperature, but the corresponding convex-shaped VT recovery process is not observed, substituted, instead, with a quick and monotonic recovery process to the initial state. To explain these interesting and different phenomena, we proposed physical mechanisms of time and temperature-dependent hole trapping, releasing, and transport, in terms of the discrepancies in barrier height and space charge region, at the metal/p-GaN junction between SG and OG HEMTs.

Implementation of Aging Mechanism Analysis and Prediction for XILINX 7-Series FPGAs with a 28-nm Process.

Commercial off-the-shelf (COTS) field-programmable gate arrays (FPGAs) with a 28-nm process have become popular devices for computing systems. Although current generation FPGAs have advantages over previous models, the phenomenon of circuit aging has become more significant with the sharp reduction in the process size of FPGAs. Aging results in FPGA performance degradation over time and, ultimately, hard faults. However, few studies have focused on understanding aging mechanisms or estimating the aging trend of 28-nm FPGAs. For this, we used a ring oscillator (RO)-based test structure to extract data and build a dataset that could be used to predict aging trends and determine the primary aging mechanisms of 28-nm FPGAs. Moreover, we proposed a correction method to correct temperature-induced measurement errors in accelerated tests. Furthermore, we employed four machine learning (ML) technologies that were based on accurate measurement datasets to predict FPGA aging trends. In the experiment, 24 XILINX 7-series FPGAs (28 nm) were evaluated for 10+ years of circuit operation using accelerated tests. The results showed that the aging effects of negative-bias temperature instability (NBTI) was the primary aging mechanism. The correction method proposed in this paper could effectively eliminate measurement errors. In addition, the minimum prediction error rate of the ML model was only 0.292%.

Investigation of Negative Bias Temperature Instability Effect in Nano PDSOI PMOSFET.

The Negative Bias Temperature Instability (NBTI) effect of partially depleted silicon-on-insulator (PDSOI) PMOSFET based on 130 nm is investigated. First, the effect of NBTI on the IV characteristics and parameter degradation of T-Gate PDSOI PMOSFET was investigated by accelerated stress tests. The results show that NBTI leads to a threshold voltage negative shift, saturate drain current reduction and transconductance degradation of the PMOSFET. Next, the relationship between the threshold voltage shift and stress time, gate bias and temperature, and the channel length is investigated, and the NBTI lifetime prediction model is established. The results show that the NBTI lifetime of a 130 nm T-Gate PDSOI PMOSFET is approximately 18.7 years under the stress of VG = -1.2 V and T = 125 °C. Finally, the effect of the floating-body effect on NBTI of PDSOI PMOSFET is investigated. It is found that the NBTI degradation of T-Gate SOI devices is greater than that of the floating-body SOI devices, which indicates that the floating-body effect suppresses the NBTI degradation of SOI devices.

Discovery and structure-activity relationships of a novel oxazolidinone class of bacterial type II topoisomerase inhibitors.

There is an increasingly urgent and unmet medical need for novel antibiotic drugs that tackle infections caused by multidrug-resistant (MDR) pathogens. Novel bacterial type II topoisomerase inhibitors (NBTIs) are of high interest due to limited cross-resistance with fluoroquinolones, however analogues with Gram-negative activity often suffer from hERG channel inhibition. A novel series of bicyclic-oxazolidinone inhibitors of bacterial type II topoisomerase were identified which display potent broad-spectrum anti-bacterial activity, including against MDR strains, along with an encouraging in vitro safety profile. In vivo proof of concept was achieved in a A. baumannii mouse thigh infection model.

A Short History of Topoisomerases at Actelion Pharmaceuticals.

The discovery of novel antibacterials devoid of cross resistance is of utmost importance. At the same time, biological pathways and processes suitable to be targeted are limited. At Actelion Pharmaceuticals we decided to work on novel bacterial topoisomerase inhibitors (NBTI) to discover new antibiotics with broad spectrum activity and limited resistance development for use against severe hospital infections. This paper summarizes the learnings and results of our efforts in the field, which led to the discovery of multiple chemical classes with potent Gram-negative activity and ultimately to the selection of several compounds that underwent preclinical profiling.

A Body of Circumstantial Evidence for the Irreversible Ectonucleotidase Inhibitory Action of FSCPX, an Agent Known as a Selective Irreversible A1 Adenosine Receptor Antagonist So Far.

In previous studies using isolated, paced guinea pig left atria, we observed that FSCPX, known as a selective A1 adenosine receptor antagonist, paradoxically increased the direct negative inotropic response to A1 adenosine receptor agonists (determined using concentration/effect (E/c) curves) if NBTI, a nucleoside transport inhibitor, was present. Based on mathematical modeling, we hypothesized that FSCPX blunted the cardiac interstitial adenosine accumulation in response to nucleoside transport blockade, probably by inhibiting CD39 and/or CD73, which are the two main enzymes of the interstitial adenosine production in the heart. The goal of the present study was to test this hypothesis. In vitro CD39 and CD73 inhibitor assays were carried out; furthermore, E/c curves were constructed in isolated, paced rat and guinea pig left atria using adenosine, CHA and CPA (two A1 adenosine receptor agonists), FSCPX, NBTI and NBMPR (two nucleoside transport inhibitors), and PSB-12379 (a CD73 inhibitor), measuring the contractile force. We found that FSCPX did not show any inhibitory effect during the in vitro enzyme assays. However, we successfully reproduced the paradox effect of FSCPX in the rat model, mimicked the "paradox" effect of FSCPX with PSB-12379, and demonstrated the lipophilia of FSCPX, which could explain the negative outcome of inhibitor assays with CD39 and CD73 dissolved in a water-based solution. Taken together, these three pieces of indirect evidence are strong enough to indicate that FSCPX possesses an additional action besides the A1 adenosine receptor antagonism, which action may be the inhibition of an ectonucleotidase. Incidentally, we found that POM-1 inhibited CD73, in addition to CD39.

Investigation of Mechanical Strains in Thermal Compensation Loop of Superconducting NbTi Cable during Bending and Cyclic Operation.

In the paper, the thermal compensation loops on a composite, superconducting NbTi cable were investigated. This type of cable is used in the superconducting, fast ramping magnets of the SIS100 synchrotron, part of the Facility for Antiproton and Ion Research (FAIR) under construction in Darmstadt, Germany. The influence of space restrictions and electromagnetic cross-talk on the design of the thermal compensation loop was discussed. Plastic deformation of cable components during bending was analyzed by numerical simulations and experiments. A three-dimensional numerical model of the cable was prepared with individual superconducting wires in contact with a central cooling pipe. The bending of a straight cable into a compensation loop shape was simulated, followed by cyclic operation of the cable during thermal cycles. The maximum strains in the superconducting strands and cooling tube were analyzed and discussed.

Characteristics, Mechanism and Criterion of Channel Segregation in NbTi Alloy via Numerical Simulations and Experimental Characterizations.

Channel segregation (CS) is the most typical defect during solidification of NbTi alloy. Based on numerical simulation and experimental characterizations, we deeply elucidated its characteristics, formation mechanism, effecting factor and prediction criterion. According to acid etching, industrial X-ray transmission imaging, 3D X-ray microtomography and chemical analysis, it was found that in a casing ingot, by He cooling, finer grain size, weaker segregation and slighter CS can be obtained compared with air-cooled ingot. The simulation results of macrosegregation show that CS is caused by the strong natural convection in the mushy zone triggered by the thermo-solutal gradient. Its formation can be divided into two stages including channel initiation and growth. In addition, due to the stronger cooling effect of the He treatment, the interdendritic flow velocity becomes smaller, consequently lowering the positive segregation and CS and improving the global homogenization of the final ingot. Finally, to predict the formation of CS, the Rayleigh number model was proposed and its critical value was found to be 15 in NbTi alloy for the first time. When it is lower than the threshold, CS disappears. It provides an effective tool to evaluate and optimize the solidification parameters to fabricate the homogenized NbTi ingot in engineering practice.

Novel bacterial topoisomerase inhibitors derived from isomannide.

A series of Novel Bacterial Topoisomerase Inhibitors (NBTIs) employing a linker derived from isomannide were synthesized and evaluated. Reduced hERG inhibition was observed compared to structure-matched analogues with different linkers, and compound 6 showed minimal proarrhythmic potential using an in vitro panel of cardiac ion channels. Compound 6 also displayed excellent activity against fluoroquinolone-resistant MRSA (MIC90 = 2 µg/mL) and other Gram-positive pathogens.

An Advanced In Silico Modelling of the Interaction between FSCPX, an Irreversible A1 Adenosine Receptor Antagonist, and NBTI, a Nucleoside Transport Inhibitor, in the Guinea Pig Atrium.

In earlier studies, we generated concentration-response (E/c) curves with CPA (N6-cyclopentyladenosine; a selective A1 adenosine receptor agonist) or adenosine, in the presence or absence of S-(2-hydroxy-5-nitrobenzyl)-6-thioinosine (NBTI, a selective nucleoside transport inhibitor), and with or without a pretreatment with 8-cyclopentyl-N3-[3-(4-(fluorosulfonyl)-benzoyloxy)propyl]-N1-propylxanthine (FSCPX, a chemical known as a selective, irreversible A1 adenosine receptor antagonist), in isolated, paced guinea pig left atria. Meanwhile, we observed a paradoxical phenomenon, i.e. the co-treatment with FSCPX and NBTI appeared to enhance the direct negative inotropic response to adenosine. In the present in silico study, we aimed to reproduce eight of these E/c curves. Four models (and two additional variants of the last model) were constructed, each one representing a set of assumptions, in order to find the model exhibiting the best fit to the ex vivo data, and to gain insight into the paradoxical phenomenon in question. We have obtained in silico evidence for an interference between effects of FSCPX and NBTI upon our ex vivo experimental setting. Regarding the mechanism of this interference, in silico evidence has been gained for the assumption that FSCPX inhibits the effect of NBTI on the level of endogenous (but not exogenous) adenosine. As an explanation, it may be hypothesized that FSCPX inhibits an enzyme participating in the interstitial adenosine formation. In addition, our results suggest that NBTI does not stop the inward adenosine flux in the guinea pig atrium completely.

Antioxidant, Anti-Lung Cancer, and Anti-Bacterial Activities of Toxicodendron vernicifluum.

This work tested antioxidant, anti-lung cancer, and antibacterial activities by in vitro, in vivo, and computational experiments for the metabolites extracted from the bark, seed, and stem of Toxicodendron vernicifluum. The results showed that all the extracts significantly scavenged 1,2-diphenyl-1-picrylhydrazyl (DPPH) in a dose-dependent manner. But, the total phenol content (TPC) ranged from 2.12 to 89.25% and total flavonoids content (TFC) ranged from 1.02 to 15.62% in the extracts. The methanolic bark extract (MBE) exhibited higher DPPH scavenging activity than the other extracts, probably due to the higher content of the TPC and TFC present in it. Among the extracts, only the MBE showed anti-lung cancer activity at an acceptable level with a therapeutic index value (22.26) against human lung carcinoma. This was due to the cancer cell death in A549 induced by MBE through reactive oxygen species (ROS) generation, apoptosis, and cell arrest in G1 phase and inhibition of anti-pro-apoptotic protein survivin. Among the extracts, MBE showed significantly higher antibacterial activity as evident through the higher zone of inhibition 13 ± 0.5 mm against methycilin resistant strain of Staphylococcus aureus (MRSA), Salmonila enteria subp. enterica, and P. aeruginosa, 11 ± 0.3 mm against E. coli and 10 ± 0.2 mm against B. cereus. The MBE also showed an excellent antibacterial activity with lower minimal inhibitory concentration (MIC). Particularly, the MBE showed more significant antibacterial activity in MRSA. The in vivo antibacterial activity of the MBE was further tested in C. elegans model. The treatment of the MRSA induced cell disruption, damage and increased mortality of C. elegans as compared to the untreated and MBE treated C. elegans with normal OP50 diet. Moreover, the MBE treatment enhanced the survival of the MRSA infected C. elegans. The compounds, such as 2,3,3-trimethyl-Octane and benzoic from the MBE, metabolized the novel bacterial topoisomerases inhibitor (NBTI) and MRSA related protein (PBP2a). Overall the T. vernicifluum is potentially bioactive as evident by antioxidant, anti-lung cancer, and antibacterial assays. Further studies were targeted on the purification of the novel compounds for the clinical evaluation.