Antibiotic-resistant Enterobacterales pose a major threat to healthcare systems worldwide, necessitating the development of novel strategies to fight such hard-to-kill bacteria. One potential ...approach is to develop molecules that force bacteria to hyper-activate prodrug antibiotics, thus rendering them more effective. In the present work, we aimed to obtain proof-of-concept data to support that small molecules targeting transcriptional regulators can potentiate the antibiotic activity of the prodrug metronidazole (MTZ) against Escherichia coli under aerobic conditions. By screening a chemical library of small molecules, a series of structurally related molecules were identified that had little inherent antibiotic activity but showed substantial activity in combination with ineffective concentrations of MTZ. Transcriptome analyses, functional genetics, thermal shift assays, and electrophoretic mobility shift assays were then used to demonstrate that these MTZ boosters target the transcriptional repressor MarR, resulting in the upregulation of the marRAB operon and its downstream MarA regulon. The associated upregulation of the flavin-containing nitroreductase, NfsA, was then shown to be critical for the booster-mediated potentiation of MTZ antibiotic activity. Transcriptomic studies, biochemical assays, and electron paramagnetic resonance measurements were then used to show that under aerobic conditions, NfsA catalyzed 1-electron reduction of MTZ to the MTZ radical anion which in turn induced lethal DNA damage in E. coli. This work reports the first example of prodrug boosting in Enterobacterales by transcriptional modulators and highlights that MTZ antibiotic activity can be chemically induced under anaerobic growth conditions.
Dimethylammonium (DMA) zinc formate is the precursor for a large family of multiferroics, materials which display co-existing magnetic and dielectric ordering. However, the mechanism underlying these ...orderings remains unclear. While it is generally believed that the dielectric transition is related to the freezing of the order–disorder dynamics of the DMA+ cation, no quantitative data on this motion are available. We surmise that this is due to the fact that the timescale of this cationic motion is on the borderline of the timescales of experimental techniques used in earlier reports. Using multifrequency electron paramagnetic resonance (EPR), we find that the timescale of this motion is ∼5 × 10 –9 s. Thus, S-band (4 GHz) EPR spectroscopy is presented as the technique of choice for studying these motional dynamics. This work highlights the value of the lower-frequency end of EPR spectroscopy. The data are interpreted using density functional theory calculations and provide direct evidence for the motional freezing model of the ferroelectric transition in these metal–organic frameworks with the ABX3 perovskite-like architecture.
The photocatalytic CO2 reduction into value‐added chemicals is regarded as one promising technology to mitigate environmental issues and the energy crisis of the modern world due to the extended CO2 ...emissions. Recent advances have shown that iron porphyrins are considered as one of the most efficient molecular catalysts in the activation and reduction of molecules like CO2. Thus, a suitably modified FeIII porphyrin (FeIII(TF4TMAP)(CF3SO3)5) was prepared and its catalytic activity in terms of photocatalytic reduction of CO2 was studied. This iron catalyst possesses four fluorine substituents in the ortho and the meta position of each meso‐phenyl group of the porphyrin, while trimethylammonium groups were placed in the para position. Photocatalytic studies were performed in the presence of an iridium complex as a chromophore and have shown that FeIII(TF4TMAP)(CF3SO3)5 can effectively reduce CO2, achieving excellent turnover numbers (up to 5500 TONs) and high turnover frequencies. The main reduction product of this photocatalytic system was CO, and only a small amount of hydrogen was detected, presenting a maximum selectivity of 86 % for CO.
Photocatalysis: This work describes photocatalytic CO2 reduction using for the first time the iron porphyrin derivative FeIII(TF4TMAP)(CF3SO3)5 as molecular catalyst. After visible light irradiation CO2 to CO conversion was observed achieving excellent turnover numbers (up to 5500 TONs) and high selectivity.
In nature, dihydrogen is catalytically produced or split by the FeFe and NiFe hydrogenases. Despite common structural features in their dinuclear active site, i.e., a thiolate-rich coordination ...sphere and CO/CN– ligation, the synergetic way, in which the two metal sites act during catalysis, is specific for each enzyme. With the aim of understanding the role of the nature of the metal (Fe vs Ni), we report on a homodinuclear FeFe complex, a parent of a previously reported NiFe complex, to compare their electrocatalytic activity for H2 production. The di-iron complex (CO)LN2S2FeIIFeII(CO)Cp+ (with LN2S2 = 2,2′-(2,2′-bipyridine-6,6′-diyl)bis(1,1-diphenylethanethiolate and Cp = cyclopentadienyl) has been synthesized and fully characterized. In the solid state, it contains two CO ligands: one bound to the {FeCp} moiety in a semibridging manner and one terminally bound to the {FeLN2S2} moiety. This dinuclear iron complex is thus not isostructural to LN2S2NiIIFeII(CO)Cp+, which contains a single CO ligand terminally bound to the Fe site. However, at low concentrations in MeCN solutions, the CO ligand coordinated to the {FeLN2S2} moiety is removed and the CO ligand bound to the {FeCp} moiety becomes fully bridging between the two Fe sites. Under such conditions, the di-iron complex displays similar catalytic performances to the parent NiFe complex (a comparable overpotential, η = 730 and 690 mV, and TON = 15 and 16, respectively). Cyclic voltammetry data give direct experimental evidence for an EECEC mechanism, which was also previously proposed for the NiFe complex. However, the structure of the one-electron reduced species, the entry point of the catalytic cycle, slightly differs for the two systems: in LN2S2NiI(CO)FeIICp, this is valence localized species on the site Ni and the CO ligand bridges the two metal ions, while in (CO)LN2S2FeFeCp, this is a type II–III mixed-valence species with the CO terminally bound to the {FeLN2S2} unit.
A series of copper/nitrosoarene complexes was created that mimics several steps in biomimetic O2 activation by copper(I). The reaction of the copper(I) complex of ...N,N,N′,N′-tetramethypropylenediamine with a series of para-substituted nitrosobenzene derivatives leads to adducts in which the nitrosoarene (ArNO) is reduced by zero, one, or two electrons, akin to the isovalent species dioxygen, superoxide, and peroxide, respectively. The geometric and electronic structures of these adducts were characterized by means of X-ray diffraction, vibrational analysis, ultraviolet–visible spectroscopy, NMR, electrochemistry, and density functional theory (DFT) calculations. The bonding mode of the NO moiety depends on the oxidation state of the ArNO moiety: κN for ArNO, mononuclear η2-NO and dinuclear μ-η2:η1 for ArNO•–, and dinuclear μ-η2:η2 for ArNO2–. 15N isotopic labeling confirms the reduction state by measuring the NO stretching frequency (1392 cm–1 for κN-ArNO, 1226 cm–1 for η2-ArNO•–, 1133 cm–1 for dinuclear μ-η2:η1-ArNO•–, and 875 cm–1 for dinuclear μ-η2:η2 for ArNO2–). The 15N NMR signal disappears for the ArNO•– species, establishing a unique diagnostic for the radical state. Electrochemical studies indicate reduction waves that are consistent with one-electron reduction of the adducts and are compared with studies performed on Cu-O2 analogues. DFT calculations were undertaken to confirm our experimental findings, notably to establish the nature of the charge-transfer transitions responsible for the intense green color of the complexes. In fine, this family of complexes is unique in that it walks through three redox states of the ArNO moiety while keeping the metal and its supporting ligand the same. This work provides snapshots of the reactivity of the toxic nitrosoarene molecules with the biologically relevant Cu(I) ion.
The Front Cover depicts photocatalytic hydrogen production in water using a series of cobalt complexes bearing redox non‐innocent ligands as molecular catalysts and carbon dots as metal‐free ...photosensitizers. After visible light irradiation, proton conversion into hydrogen was observed, with great activity (up to 570 TONs) and high stability. We are grateful to Dr. Sylvain Bertaina for his assistance in the design of the cover illustration. More information can be found in the Research Article by K. Ladomenou, A. G. Coutsolelos, M. Orio and co‐workers.
The stereoselective copper‐mediated hydroxylation of intramolecular C−H bonds from tridentate ligands is reinvestigated using DFT calculations. The computational study aims at deciphering the ...mechanism of C−H hydroxylation obtained after reaction of Cu(I) precursors with dioxygen, using ligands bearing either activated (L1) or non‐activated (L2) C−H bonds. Configurational analysis allows rationalization of the experimentally observed regio‐ and stereoselectivity. The computed mechanism involves the formation of a side‐on peroxide species (P) in equilibrium with the key intermediate bis‐(μ‐oxo) isomer (O) responsible for the C−H activation step. The P/O equilibrium yields the same activation barrier for the two complexes. However, the main difference between the two model complexes is observed during the C−H activation step, where the complex bearing the non‐activated C−H bonds yields a higher energy barrier, accounting for the experimental lack of reactivity of this complex under those conditions.
Computational insights on reactivity: The stereoselective copper‐mediated intramolecular C−H bond hydroxylation is investigated using DFT calculations. The computed mechanism involves a dinuclear side‐on μ‐η2:η2‐peroxo dicopper(II) adduct in equilibrium with the key oxidizing intermediate bis(μ‐oxo) dicopper(III) species. The difference of reactivity towards internal substrates bearing activated or non‐activated C−H bonds is rationalized.
Combining different molecular switching functions in a single molecule is a simple strategy to develop commutable molecules featuring more than two commutation states. The present study reports on ...two molecular systems consisting of two indolino-oxazolidine (Box) moieties connected to an aromatic bridge (phenyl or bithiophene) by ethylenic junctions. Such systems, referenced as BiBox, are expected to show up multiaddressable and multiresponsive behaviors. On one hand, the oxazolidine ring opening/closure of Box moieties can be addressed by chemical stimuli, and on the other hand, the trans-to-cis isomerization of the ethylenic junctions is induced by visible light irradiation (with a thermal back conversion). NMR and UV–visible spectroscopies allowed to characterize up to nine out of the ten theoretically expected commutation states as well as to measure the kinetics of the interconversions. Also, steady state fluorescence spectroscopy measurements highlighted the strong influence of the open/closed states of the Box moieties on their emission properties.
Dimethylammonium zinc formate ((CH3)2NH2Zn(HCOO)3 or DMZnF) is a model system for the study of hybrid perovskite-like dielectrics. It undergoes a phase transition from the paraelectric to ...ferroelectric phase at ∼166 K, as observed via NMR spectra. The mechanism of this phase transition has been shown to have contributions from ordering of the hydrogen bonds between (CH3)2NH2+ (DMA+) and the formate groups as well as buckling of the metal-formate framework, but the transition dynamics and atomistic mechanism are not fully clear. This work presents dielectric constant measurements as evidence of cluster formation of the low-temperature phase and the relaxor-like behavior of this metal–organic framework above the phase transition temperature. 13C CP-MAS is used to track the evolution of the chemical shift, T 1, and T 2 of the dimethylammonium cation and formate groups from room temperature to 120 K. 2D 13C–13C correlation measurements provide evidence of the formation of pretransitional clusters above the phase transition temperature. Density functional theory (DFT) calculations support the assignment of chemical shifts and the proposed model. The analysis of 13C CP-MAS spectra and DFT calculations is used to discuss the mechanism of the dielectric phase transition and the origin of relaxor-like behavior in DMZnF.
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