Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding

Antimicrobial resistance in Gram-negative bacteria is one of the greatest threats to global health. New antibacterial strategies are urgently needed, and the development of antibiotic adjuvants that either neutralize resistance proteins or compromise the integrity of the cell envelope is of ever-growing interest. Most available adjuvants are only effective against specific resistance proteins. Here we demonstrate that disruption of cell envelope protein homeostasis simultaneously compromises several classes of resistance determinants. In particular, we find that impairing DsbA-mediated disulfide bond formation incapacitates diverse β-lactamases and destabilizes mobile colistin resistance enzymes. Furthermore, we show that chemical inhibition of DsbA sensitizes multidrug-resistant clinical isolates to existing antibiotics and that the absence of DsbA, in combination with antibiotic treatment, substantially increases the survival of Galleria mellonella larvae infected with multidrug-resistant Pseudomonas aeruginosa. This work lays the foundation for the development of novel antibiotic adjuvants that function as broad-acting resistance breakers.

Breaking antimicrobial resistance by disrupting extracytoplasmic protein folding

Antimicrobial resistance in Gram-negative bacteria is one of the greatest threats to global health. New antibacterial strategies are urgently needed, and the development of antibiotic adjuvants that either neutralize resistance proteins or compromise the integrity of the cell envelope is of ever-growing interest. Most available adjuvants are only effective against specific resistance proteins. Here we demonstrate that disruption of cell envelope protein homeostasis simultaneously compromises several classes of resistance determinants. In particular, we find that impairing DsbA-mediated disulfide bond formation incapacitates diverse β-lactamases and destabilizes mobile colistin resistance enzymes. Furthermore, we show that chemical inhibition of DsbA sensitizes multidrug-resistant clinical isolates to existing antibiotics and that the absence of DsbA, in combination with antibiotic treatment, substantially increases the survival of Galleria mellonella larvae infected with multidrug-resistant Pseudomonas aeruginosa. This work lays the foundation for the development of novel antibiotic adjuvants that function as broad-acting resistance breakers.

Sequestration of Plant Defense Compounds by Insects: From Mechanisms to Insect–Plant Coevolution

Plant defense compounds play a key role in the evolution of insect–plant associations by selecting for behavioral, morphological, and physiological insect adaptations. Sequestration, the ability of herbivorous insects to accumulate plant defense compounds to gain a fitness advantage, represents a complex syndrome of adaptations that has evolved in all major lineages of herbivorous insects and involves various classes of plant defense compounds. In this article, we review progress in understanding how insects selectively accumulate plant defense metabolites and how the evolution of specific resistance mechanisms to these defense compounds enables sequestration. These mechanistic considerations are further integrated into the concept of insect–plant coevolution. Comparative genome and transcriptome analyses, combined with approaches based on analytical chemistry that are centered in phylogenetic frameworks, will help to reveal adaptations underlying the sequestration syndrome, which is essential to understanding the influence of sequestration on insect–plant coevolution.

Comparison of different infiltration amounts of CeO2 inside Ni-YSZ anodes to improve stability and efficiency of Single-Chamber SOFCs operating in methane

Electrochemically active oxide-based anodes capable of working in Single-Chamber Solid Oxide Fuel Cells (SC-SOFCs) were developed. Their performance is related to the selectivity of the electrodes. Tests are carried out on lab-scale devices with YSZ pellets as solid electrolytes in electrolyte supported cells. Selecting methane as a fuel, a gas mixture in the ratio CH4/O2 = 2 was chosen. The Ni-YSZ (NiO:YSZ=60:40) anode was optimized through CeO2 nanocatalysts infiltration to enhance the anode catalytic activity and make its reduction easier. Several infiltration amounts were compared, from null to 15% of the electrode weight. Both symmetric and complete cells (with LSCF-based cathodes) were tested in H2 and CH4/O2. For increasing amounts of infiltrated CeO2, symmetric cells tests describe an area specific resistance (ASR) reduction from 40 Ω cm2 to 1.7 Ω cm2 in hydrogen and from 11 Ω cm2 to 3.9 Ω cm2 in the methane/oxygen mixture. While complete cells tests displayed an ASR drop from 30 Ω cm2 to 2.9 Ω cm2 in H2, and from 8.7 Ω cm2 to 4.3 Ω cm2 in the methane/oxygen mixture, while OCP and power grew from 478 mV and 3.7 mW cm-2 to 766 mV and 13 mW cm-2.

Specific Resistance Resources in the Salutogenic Model of Health

This chapter discusses conceptual and concrete differences between generalized and specific resistance resources in the salutogenic model of health. It is important to distinguish between the two types of resistance resources to ensure that health promotion pays attention to both types. Specific resistance resources have as much or more relevance to health promotion practice as do generalized resistance resources. By drawing attention to the nature of specific resistance resources, one also draws attention to what should be the main aim of health promotion.

The Interferon Resistance of Transmitted HIV-1 is a Consequence of Enhanced Replicative Fitness

HIV-1 transmission via sexual exposure is a relatively inefficient process. When successful transmission does occur, newly infected individuals are colonized by either a single or a very small number of establishing virion(s). These transmitted founder (TF) viruses are more interferon (IFN) resistant than chronic control (CC) viruses present 6 months after transmission. To identify the specific molecular defences that make CC viruses more susceptible to the IFN-induced ′antiviral state′ than TF viruses, we established a pair of fluorescent GFP-IRES-Nef TF and CC viruses and used arrayed interferon-stimulated gene (ISG) expression screening. The relatively uniform ISG resistance of transmitted HIV-1 directed us to investigate the underlying mechanism. Our subsequent in silico simulations, modelling, and in vitro characterisation of a model TF/CC pair (closely matched in replicative fitness), revealed that small differences in replicative growth rates can explain the broad IFN resistance displayed by transmitted HIV-1. We propose that the apparent IFN resistance of transmitted HIV-1 is a consequence of enhanced replicative fitness, as opposed to specific resistance to individual IFN-induced defences.

Effects of Resistance Training With Constant, Inertial, and Combined Loads on Muscle Power and Strength Output

The aim of this study was to investigate the resistance-specific gains in muscle power and strength (1RM) following the training of maximum bench-press throws (BPT) against constant, inertial, and combined resistance. Forty-eight male participants (age 20.5 ± 2.0 years) were randomly assigned to the constant, inertial, combined resistance, or control group. Participants underwent 8 weeks of training of BPT against the loads that corresponded to the different effects of mass of 40 kg (∼50% of 1RM). The gains in average and maximum power, and 1RM were significant in all experimental groups (P < 0.01), but not in the control group (P > 0.1). Relative gains in the average (26.3 ± 9.8%) and maximum power (25.2 ± 9.8%) were larger than that in the 1RM (mean 7.2 ± 6.9%; both P < 0.001). The gains in the average (F4, 66 = 6.0; P < 0.01) and maximum power (F4, 66 = 4.7; P < 0.01) were higher when tested against the training-specific resistance than when tested against the remaining two resistance types. Differences in 1RM among experimental groups were not significant (P = 0.092). The most important and rather novel finding of the study is that the training against the weight and inertial resistance, and their combination results in resistance-specific gains in muscle power, although the overall gains muscle strength and power remain comparable across the training protocols.

Electrochemical properties of La9.33Si6O26(LSO)-La0.8Sr0.2Ga0.8Mg0.2O2.55(LSGM) electrolyte over NiO and La0.1Ca0.9MnO3(LCM) electrodes

The electrochemical properties of La9.33Si6O26(LSO)-La0.8Sr0.2Ga0.8Mg0.2O2.55(LSGM) electrolyte composites have been evaluated over NiO and La0.1Ca0.9MnO3 (LCM) electrodes using symmetric and asymmetrical cells of NiO/LSO-LSGM/NiO and NiO/LSO-LSGM/LCM, respectively. The Nyquist plot obtained from this study suggested that the new electrolyte system exhibits excellent performance over the NiO and LCM electrodes and shows an ideal Randel cell electrical circuit characteristic in both NiO/LSO-LSGM/NiO and NiO/LSO-LSGM/LCM cells. The area-specific resistance (ASR) and, the activation energy (Ea) of NiO/LSO-LSGM/NiO from the Arrhenius plot are lower than the NiO/LSO-LSGM/LCM, which is 0.30 Ω cm-2 and of 0.74 eV versus 0.40 Ω cm-2 with Ea of 0.76 eV, respectively.

The Effect of Current Supply Duration during Stepwise Electrical Sintering of Silver Nanoparticles

We studied the effect of current supply duration at final-step currents during the stepwise electrical sintering of silver (Ag) nanoparticles (NPs). Ag NPs ink was inkjet-printed onto Eagle-XG glass substrates. Constant final-step currents of 0.4 and 0.5 A with various time intervals were applied to the printed samples. The final-step current of 0.5 A damaged the line at a comparatively shorter time duration. On the other hand, the lower final-step current of 0.4 A prevented the line damage at longer time durations while producing comparatively lower Ag NPs specific resistance. The minimum specific resistances of the printed samples sintered at 0.4 and 0.5 A were 3.59 μΩ∙cm and 3.79 μΩ∙cm, respectively. Furthermore, numerical temperature estimation and scanning electron microscope (SEM) analysis were conducted to elaborate on the results. The numerical temperature estimation results implied that the lower estimated peak temperature at the final-step current of 0.4 A helped prevent Ag NP line damage. The SEM micrographs suggested that a high surface porosity—caused by higher sintering peak temperatures—in the case of the 0.5 A final-step current resulted in a comparatively higher Ag NP line-specific resistance. This contribution is a step forward in the development of Ag NP sintering for printed electronics applications.

Microbial Efflux Pump Inhibitors: A Journey around Quinoline and Indole Derivatives

Antimicrobial resistance (AMR) is a complex threat to human health and, to date, it represents a hot topic in drug discovery. The use of non-antibiotic molecules to block resistance mechanisms is a powerful alternative to the identification of new antibiotics. Bacterial efflux pumps exert the early step of AMR development, allowing the bacteria to grow in presence of sub-inhibitory drug concentration and develop more specific resistance mechanisms. Thus, efflux pump inhibitors (EPIs) offer a great opportunity to fight AMR, potentially restoring antibiotic activity. Based on our experience in designing and synthesizing novel EPIs, herein, we retrieved information around quinoline and indole derivatives reported in literature on this topic. Thus, our aim was to collect all data around these promising classes of EPIs in order to delineate a comprehensive structure–activity relationship (SAR) around each core for different microbes. With this review article, we aim to help future research in the field in the discovery of new microbial EPIs with improved activity and a better safety profile.