Discovering targeted inhibitors for Escherichia coli efflux pump fusion proteins using computational and structure‐guided approaches

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Discovering targeted inhibitors for Escherichia coli efflux pump fusion proteins using computational and structure-guided approaches

Antimicrobial resistance has become a global health concern because of the rapid evolution of multidrug-resistant microbes and the delayed development of new medications. Microbes have a variety of molecular resistance mechanisms; one of them is the presence of efflux pumps. Considering E. coli as a model organism, we have identified potential AcrAB-TolC inhibitors by performing molecular docking and density functional theory (DFT) calculations to get insight into the binding model. These identified compounds could pose a better inhibitor and provide a potential approach for stimulating the actions of antibiotics in resistant bacteria.


Abstract

Multidrug resistance pathogens causing infections and illness remain largely untreated clinically. Efflux pumps are one of the primary processes through which bacteria develop resistance by transferring antibiotics from the interior of their cells to the outside environment. Inhibiting these pumps by developing efficient derivatives appears to be a promising strategy for restoring antibiotic potency. This investigation explores literature-reported inhibitors of E. coli efflux pump fusion proteins AcrB-AcrA and identify potential chemical derivatives of these inhibitors to overcome the limitations. Using computational and structure-guided approaches, a study was conducted with the selected inhibitors (AcrA:25-AcrB:59) obtained by data mining and their derivatives (AcrA:857-AcrB:3891) to identify their inhibitory effect on efflux pump using virtual screening, molecular docking and density functional theory (DFT) calculations. The finding indicates that Compound 2 (ZINC000072136376) has shown better binding and a significant inhibitory effect on AcrA, while Compound 3 (ZINC000072266819) has shown stronger binding and substantial inhibition effect on both non-mutant and mutated AcrB subunits. The identified derivatives could exhibit a better inhibitor and provide a potential approach for restoring the actions of resistant antibiotics.

Ag‐based bimetallic clusters as catalysts for p‐nitrophenol reduction by glycerol: A DFT investigation

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Ag-based bimetallic clusters as catalysts for p-nitrophenol reduction by glycerol: A DFT investigation

DFT calculation of Ni@Ag cluster interacting simultaneously with p-nitrophenol and glycerol molecules.


Abstract

Reducing p-nitrophenol (PNP) to p-aminophenol is an industrially relevant synthesis. Nevertheless, only a few heterogeneous catalysts have been evaluated for the reduction of PNP by glycerol. Appropriate quantum computational studies can screen potential catalysts for this crucial green reaction. The present research investigates the catalytic activities of Pd@Ag and Ni@Ag core-shell nanogeometries toward PNP reduction by glycerol through density functional theory (DFT) calculations. The central atom of a geometry-optimized 13-atom Ag cluster was replaced by Pd and Ni atoms to create the core-shell morphologies. The interaction energies of PNP and glycerol with each of the (metal/bimetallic) clusters were evaluated by DFT calculations to find the best PNP and glycerol molecule orientation with the respective bimetallic cluster. Electrostatic potential surface and natural bond orbital analyses were performed to study the charge distribution and transfer between atomic orbitals. The frequencies of vibrational modes in isolated PNP/glycerol structures were compared to those when these molecules were in the presence of the different metal clusters to infer the effect of the interactions. All performed analyses indicated improved catalytic activity toward PNP reduction by glycerol upon Ni-doping of the Ag13 cluster.

Cooperative Bimetallic Co−Mn Catalyst: Exploiting Metallo‐Organic and Hydrogen Bonded Interactions for Rechargeable C‐/N‐Alkylation

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Cooperative Bimetallic Co−Mn Catalyst: Exploiting Metallo-Organic and Hydrogen Bonded Interactions for Rechargeable C-/N-Alkylation

Disclosed, herein, a flexible multidentate ligand (L) for Co/Mn-based supramolecular materials, serving as a reusable catalyst for C-/N-alkylation of alcohols with higher reaction efficiency and selectivity compared to individual components via its flexible binding sites, diverse hydrogen bond donor-acceptor fragments, rigidity, variable coordination mode, and cooperativity.


Abstract

Despite the progress on cobalt and manganese catalyzed C−C and C−N bond-forming methodologies, the associated catalyst reusability remains with some unresolved issue, which needs to be addressed. Disclosed herein, a flexible multidentate proton-responsive ligand (L) bearing 2,6-bis(1H-benzo[d]imidazol-2-yl)pyridine (BBP), 6-(1H-benzo[d]imidazol-2-yl)picolinic acid (BPA), and benzene-1,2-diamine (BDA) for Co/Mn-based mono- and bi-metallic supramolecular materials for C-/N-alkylation of alcohols. The flexible binding sites and different hydrogen bond donor-acceptor fragments of L brings the rigidity and self-assembling to ordered crystalline supramolecular materials, which prevented the coordinatively saturated active sites and thus providing much higher reaction efficiency and selectivity, which is highly unlikely in the case of comparable individual components. The easy synthesis, efficient reactivity and selectivity through cooperativity, broad substrate scope, and efficient recycling via recharging of metals make the catalyst and the protocol economical and sustainable. Importantly, the design strategy based on metallo-organic hydrogen bonded coordination assembly has the potential to contribute to the development of supramolecular materials for various advanced catalytic applications.

Bioengineered Lactate Oxidase Mutants for Enhanced Electrochemical Performance at Acidic pH

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Bioengineered Lactate Oxidase Mutants for Enhanced Electrochemical Performance at Acidic pH

Lactate oxidase was engineered by site-directed mutagenesis to improve the biosensor performance for lactate detection at low pH. After rational design to modulate the pKa of the catalytic His 265, the S175A variant showed higher sensitivity than the lacerate oxidase wild-type.


Abstract

Electrochemical lactate biosensors based on lactate oxidase (LOx) are used for diagnostics, sports medicine, and the food industry. However, samples from these sectors may have acidic levels at which the biocatalytic activity of LOx may be diminished. In this work, the enhancement of the bio-electrocatalytic activity of LOx at low pH by pKa modulation of its catalytic His265 was studied by rational engineering of lactate oxidase from Aerococcus viridans (AvLOx). Several candidates based on interactions with His265 were selected by in silico structural analysis. The designed variants were heterologously produced, and the S175A mutant showed considerable improvement over its wild-type counterpart, showing 157 % of the enzymatic activity found in the wild-type at pH 5. Bioelectrodes were assembled based on Prussian-blue-modified carbon paper mediator system. The electrocatalytic performance of the amperometric biosensors of S175A variant at pH 5 exhibited a linear range of 0.2–2 mM measured at 0 V vs SCE, a sensitivity of −17.52 μA/mM ⋅ cm2, representing 240 % of the sensitivity found in the wild-type biosensor, and a limit of detection of 38 μM, lower than observed with the wild-type enzyme. These results show that the mutant obtained offers a significant improvement in lactate biosensing at low pH.

Soluble Ruthenium Phthalocyanines as Semiconductors for Organic Thin‐Film Transistors

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Soluble Ruthenium Phthalocyanines as Semiconductors for Organic Thin-Film Transistors

Ruthenium phtalocyanines (RuPcs) possess distinct photoelectronic properties and a broad synthetic scope allowing for highly tuneable molecular designs, making them promising candidates as organic semiconductors in OTFTs. However, RuPcs have been underexplored in this field, and more studies are needed to provide basic insight into their potential. Herein, two novel RuPc derivatives were synthesized and implemented in OTFTs displaying p-type device operation.


Abstract

Ruthenium phthalocyanine (RuPcs) are multipurpose compounds characterized by their remarkable reactivity and photoelectronic properties, which yield a broad synthetic scope and easy derivatization at the axial position. However, RuPcs have been underexplored for use in organic thin-film transistors (OTFTs), and therefore new studies are necessary to provide basic insight and a first approach in this new application. Herein, two novel RuPc derivatives, containing axial pyridine substituents with aliphatic chains (RuPc(CO)(PyrSiC6) (1) and RuPc(PyrSiC6)2 (2), were synthesized, characterized, and tested as the organic semiconductor in OTFTs. RuPc thin-films were characterized by X-ray diffraction (XRD), and atomic force microscopy (AFM) to assess film morphology and microstructure. 1 displayed comparable p-type device performance to other phthalocyanine-based OTFTs of similar design, with an average field effect mobility of 2.08×10−3 cm2 V−1 s−1 in air and 1.36×10−3 cm2 V−1 s−1 in nitrogen, and threshold voltages from −11 V to −20 V. 2 was found to be non-functional as the semiconductor in the device architecture used, likely as a result of significant differences in thin-film formation. The results of this work illustrate a promising starting point for future development of RuPc electronic devices, particularly in this new family of OTFTs.

High Conductivity and Rate Capability of NaNb13O33 Wadsley–Roth Phase as a Fast‐Charging Li‐Ion Anode

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High Conductivity and Rate Capability of NaNb13O33 Wadsley–Roth Phase as a Fast-Charging Li-Ion Anode

The NaNb13O33 Wadsley–Roth structured phase is studied for enabling fast charging in Li-ion batteries. The material exhibits good lithium intercalation capacity of 233 mAh/g corresponding to Li15NaNb13O33 and rate capability. Multiple peaks are observed in the differential capacity plot indicating the formation of two-phase regions during intercalation of lithium. In comparison to widely studied TiNb2O7, NaNb13O33 shows faster Li-ion diffusivity particularly at high states of lithiation.


Abstract

The synthesis and electrochemical insertion of lithium into the Wadsley–Roth NaNb13O33 phase is studied. Lithium intercalation to form LixNaNb13O33 reaches a value of up to x~15, between 3.0 and 1.0 V vs. Li+/Li at a slow cycling rate, a capacity of 233 mAh g−1. Within this voltage window, two sharp peaks and one broad peak are observed in the differential capacity plots of lithium intercalation suggesting multiple two-phase regions. High Li-ion conductivity and rate capability was demonstrated. The lithium diffusion constant is about an order of magnitude greater than TiNb2O7. The average voltage is about 1.6 V and its high-rate capability makes NaNb13O33 potentially useful as an anode in a fast-charge Li-ion battery application.

Ru‐Based Organometallic Agents Bearing Phenyl Hydroxide: Synthesis and Antibacterial Mechanism Study against Staphylococcus aureus

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Ru-Based Organometallic Agents Bearing Phenyl Hydroxide: Synthesis and Antibacterial Mechanism Study against Staphylococcus aureus

Ru-based antibacterial agents, which can kill bacteria by releasing ROS and damaging bacterial cell membrane integrity, were developed. Ru (II)-1 not only showed low toxicity, but also has strong antibacterial potency against S. aureus in vivo.


Abstract

The development of antimicrobial agents with novel model of actions is a promising strategy to combat multiple resistant bacteria. Here, three ruthenium-based complexes, which acted as potential antimicrobial agents, were synthesized and characterized. Importantly, three complexes all showed strong bactericidal potency against Staphylococcus aureus. In particular, the most active one has a MIC of 6.25 μg/mL. Mechanistic studies indicated that ruthenium complex killed S. aureus by releasing ROS and damaging the integrity of bacterial cell membrane. In addition, the most active complex not only could inhibit the biofilm formation and hemolytic toxin secretion of S. aureus, but also serve as a potential antimicrobial adjuvant as well, which showed synergistic effects with eight traditional antibiotics. Finally, both G. mellonella larva infection model and mouse skin infection model all demonstrated that ruthenium complex also showed significant efficacy against S. aureus in vivo. In summary, our study suggested that ruthenium-based complexes bearing a phenyl hydroxide are promising antimicrobial agents for combating S. aureus.

Interfacial Coupling of Graphene with Nickel Nanoparticles for Water Splitting and Urea Oxidation: A Spectroelectrochemical Investigation

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Interfacial Coupling of Graphene with Nickel Nanoparticles for Water Splitting and Urea Oxidation: A Spectroelectrochemical Investigation

Efficient HER, OER, and UOR catalytic properties are achieved by interfacial coupling of 2D graphene and Ni-nano particles. Spectro-electrochemical study of Ni/graphene films of various stoichiometry reveals the dependence of the catalytic property on the synergistic interactions of graphene with Ni-nano particles.


Abstract

Nickel nanoparticle and graphene interfaces of various stoichiometries were created through electrodeposition techniques. The catalytic behavior of the electrodeposited films was investigated through spectro-electrochemical methodologies. UV-vis absorbance spectra of the electrodeposited films are significantly different in the air and alkaline medium. Furthermore, UV-vis and Raman spectroscopy confirmed the coupling of Ni nanoparticles (Ni-NP) with the graphene framework, along with NiO and Ni(OH)2. A combination of Raman and impedance spectroscopy revealed that the surface adsorption and charge transfer properties of the electrodeposited films are entirely dependent on the defects on graphene structure as well as distribution of Ni-NP on graphene. The electrodeposited films possess heterogeneous catalytic properties with a low overpotential of 50 mV (10 mA/cm−2) for hydrogen evolution reaction, as well as 601 mV and 391 mV (at 50 mA/cm−2) for the oxygen evolution reaction and urea oxidation reaction, respectively. In addition, eelectrodeposited samples show extraordinary overall water splitting performance by achieving a current density of 10 mA/cm2 at a very low applied potential of 1.38 V. This synergistic coupling of Ni and graphene renders the electrodeposited samples promising candidates as electrodes for overall water splitting in alkaline and urea-supplemented solutions.