Synergistic effect of Ru(II)-based type II photodynamic therapy with cefotaxime on clinical isolates of ESBL-producing Klebsiella pneumoniae.

Multidrug-resistant bacteria, such as ESBL producing-Klebsiella pneumoniae, have increased substantially, encouraging the development of complementary therapies such as photodynamic inactivation (PDI). PDI uses photosensitizer (PS) compounds that kill bacteria using light to produce reactive oxygen species. We test Ru-based PS to inhibit K. pneumoniae and advance in the characterization of the mode of action. The PDI activity of PSRu-L2, and PSRu-L3, was determined by serial micro dilutions exposing K. pneumoniae to 0.612 J/cm 2 of light dose. PS interaction with cefotaxime was determined on a collection of 118 clinical isolates of K. pneumoniae. To characterize the mode of action of PDI, the bacterial response to oxidative stress was measured by RT-qPCR. Also, the cytotoxicity on mammalian cells was assessed by trypan blue exclusion. Over clinical isolates, the compounds are bactericidal, at doses of 8 µg/mL PSRu-L2 and 4 µg/mL PSRu-L3, inhibit bacterial growth by 3 log10 (>99.9%) with a lethality of 30 min. A remarkable synergistic effect of the PSRu-L2 and PSRu-L3 compounds with cefotaxime increased the bactericidal effect in a subpopulation of 66 ESBL-clinical isolates to > 6 log10 with an FIC-value of 0.16 and 0.17, respectively. The bacterial transcription response suggests that the mode of action occurs through Type II oxidative stress. The upregulation of the extracytoplasmic virulence factors mrkD, magA, and rmpA accompanied this response. Also, the compounds show little or no toxicity in vitro on HEp-2 and HEK293T cells. Through the type II effect, PSs compounds are bactericidal, synergistic on K. pneumoniae, and have low cytotoxicity in mammals.

Deciphering Electronic and Structural Effects in Copper Corrole/Graphene Hybrids.

Non-covalent hybrid materials based on graphene and A3 -type copper corrole complexes were computationally investigated. The corroles complexes contain strong electron-withdrawing fluorinated substituents at the meso positions. Our results show that the non-innocent character of corrole moiety modulates the structural, electronic, and magnetic properties once the hybrid systems are held. The graphene-corrole hybrids displayed outstanding stability via the interplay of dispersion and electrostatic driving forces, while graphene act as an electron reservoir. The hybrid structures exposed an intriguing magneto-chemical performance, compared to the isolated counterparts, that evidenced how structural and electronic effects contributed to the magnetic response for both ferromagnetic and antiferromagnetic cases. Directional spin polarization and spin transfer from the corrole to the graphene surface participate in the amplification. Finally, there are relations between the spin transfer, the magnetic response, and the copper distorted ligand field, offering exciting hints about modulating the magnetic response. Therefore, this work shows that copper corroles emerged as versatile building blocks for graphene hybrid materials, especially in applications requiring a magnetic response.

Synthesis and Characterization of Iridium(III) Complexes with Substituted Phenylimidazo(4,5-f)1,10-phenanthroline Ancillary Ligands and Their Application in LEC Devices.

In this work, we report on the synthesis and characterization of six new iridium(III) complexes of the type [Ir(C^N)2(N^N)]+ using 2-phenylpyridine (C1-3) and its fluorinated derivative (C4-6) as cyclometalating ligands (C^N) and R-phenylimidazo(4,5-f)1,10-phenanthroline (R = H, CH3, F) as the ancillary ligand (N^N). These luminescent complexes have been fully characterized through optical and electrochemical studies. In solution, the C4-6 series exhibits quantum yields (Ф) twice as high as the C1-3 series, exceeding 60% in dichloromethane and where 3MLCT/3LLCT and 3LC emissions participate in the phenomenon. These complexes were employed in the active layer of light-emitting electrochemical cells (LECs). Device performance of maximum luminance values of up to 21.7 Lx at 14.7 V were observed for the C2 complex and long lifetimes for the C1-3 series. These values are counterintuitive to the quantum yields observed in solution. Thus, we established that the rigidity of the system and the structure of the solid matrix dramatically affect the electronic properties of the complex. This research contributes to understanding the effects of the modifications in the ancillary and cyclometalating ligands, the photophysics of the complexes, and their performance in LEC devices.

Theoretical Approach for the Luminescent Properties of Ir(III) Complexes to Produce Red-Green-Blue LEC Devices.

With an appropriate mixture of cyclometalating and ancillary ligands, based on simple structures (commercial or easily synthesized), it has been possible to design a family of eight new Ir(III) complexes (1A, 1B, 2B, 2C, 3B, 3C, 3D and 3E) useful as luminescent materials in LEC devices. These complexes involved the use of phenylpyridines or fluorophenylpyridines as cyclometalating ligands and bipyridine or phenanthroline-type structures as ancillary ligands. The emitting properties have been evaluated from a theoretical approach through Density Functional Theory and Time-Dependent Density Functional Theory calculations, determining geometric parameters, frontier orbital energies, absorption and emission energies, injection and transport parameters of holes and electrons, and parameters associated with the radiative and non-radiative decays. With these complexes it was possible to obtain a wide range of emission colours, from deep red to blue (701-440 nm). Considering all the calculated parameters between all the complexes, it was identified that 1B was the best red, 2B was the best green, and 3D was the best blue emitter. Thus, with the mixture of these complexes, a dual host-guest system with 3D-1B and an RGB (red-green-blue) system with 3D-2B-1B are proposed, to produce white LECs.

Thermally activated delayed fluorescence in luminescent cationic copper(i) complexes.

In this work, the photophysical characteristics of [Cu(N^N)2]+ and [Cu(N^N)(P^P)]+ complexes were described. The concept of thermally activated delayed fluorescence (TADF) and its development throughout the years was also explained. The importance of ΔE (S1-T1) and spin-orbital coupling (SOC) values on the TADF behavior of [Cu(N^N)2]+ and [Cu(N^N)(P^P)]+ complexes is discussed. Examples of ΔE (S1-T1) values reported in the literature were collected and some trends were proposed (e.g. the effect of the substituents at the 2,9 positions of the phenanthroline ligand). Besides, the techniques (or calculation methods) used for determining ΔE (S1-T1) values were described. The effect of SOC in TADF was also discussed, and examples of the determination of SOC values by DFT and TD-DFT calculations are provided. The last chapter covers the applications of [Cu(N^N)2]+ and [Cu(N^N)(P^P)]+ TADF complexes and the challenges that are still needed to be addressed to ensure the industrial applications of these compounds.

Effective Treatment against ESBL-Producing Klebsiella pneumoniae through Synergism of the Photodynamic Activity of Re (I) Compounds with Beta-Lactams.

BACKGROUND: Extended-spectrum beta-lactamase (ESBL) and carbapenemase (KPC+) producing Klebsiella pneumoniae are multidrug-resistant bacteria (MDR) with the highest risk to human health. The significant reduction of new antibiotics development can be overcome by complementing with alternative therapies, such as antimicrobial photodynamic therapy (aPDI). Through photosensitizer (PS) compounds, aPDI produces local oxidative stress-activated by light (photooxidative stress), nonspecifically killing bacteria. METHODOLOGY: Bimetallic Re(I)-based compounds, PSRe-µL1 and PSRe-µL2, were tested in aPDI and compared with a Ru(II)-based PS positive control. The ability of PSRe-µL1 and PSRe-µL2 to inhibit K. pneumoniae was evaluated under a photon flux of 17 µW/cm2. In addition, an improved aPDI effect with imipenem on KPC+ bacteria and a synergistic effect with cefotaxime on ESBL producers of a collection of 118 clinical isolates of K. pneumoniae was determined. Furthermore, trypan blue exclusion assays determined the PS cytotoxicity on mammalian cells. RESULTS: At a minimum dose of 4 µg/mL, both the PSRe-µL1 and PSRe-µL2 significantly inhibited in 3log10 (>99.9%) the bacterial growth and showed a lethality of 60 and 30 min of light exposure, respectively. Furthermore, they were active on clinical isolates of K. pneumoniae at 3-6 log10. Additionally, a remarkably increased effectiveness of aPDI was observed over KPC+ bacteria when mixed with imipenem, and a synergistic effect from 3 to 6log10 over ESBL producers of K. pneumoniae clinic isolates when mixed with cefotaxime was determined for both PSs. Furthermore, the compounds show no dark toxicity and low light-dependent toxicity in vitro to mammalian HEp-2 and HEK293 cells. CONCLUSION: Compounds PSRe-µL1 and PSRe-µL2 produce an effective and synergistic aPDI effect on KPC+, ESBL, and clinical isolates of K. pneumoniae and have low cytotoxicity in mammalian cells.

Effective Photodynamic Therapy with Ir(III) for Virulent Clinical Isolates of Extended-Spectrum Beta-Lactamase Klebsiella pneumoniae.

BACKGROUND: The extended-spectrum beta-lactamase (ESBL) Klebsiella pneumoniae is one of the leading causes of health-associated infections (HAIs), whose antibiotic treatments have been severely reduced. Moreover, HAI bacteria may harbor pathogenic factors such as siderophores, enzymes, or capsules, which increase the virulence of these strains. Thus, new therapies, such as antimicrobial photodynamic inactivation (aPDI), are needed. METHOD: A collection of 118 clinical isolates of K. pneumoniae was characterized by susceptibility and virulence through the determination of the minimum inhibitory concentration (MIC) of amikacin (Amk), cefotaxime (Cfx), ceftazidime (Cfz), imipenem (Imp), meropenem (Mer), and piperacillin-tazobactam (Pip-Taz); and, by PCR, the frequency of the virulence genes K2, magA, rmpA, entB, ybtS, and allS. Susceptibility to innate immunity, such as human serum, macrophages, and polymorphonuclear cells, was tested. All the strains were tested for sensitivity to the photosensitizer PSIR-3 (4 µg/mL) in a 17 µW/cm2 for 30 min aPDI. RESULTS: A significantly higher frequency of virulence genes in ESBL than non-ESBL bacteria was observed. The isolates of the genotype K2+, ybtS+, and allS+ display enhanced virulence, since they showed higher resistance to human serum, as well as to phagocytosis. All strains are susceptible to the aPDI with PSIR-3 decreasing viability in 3log10. The combined treatment with Cfx improved the aPDI to 6log10 for the ESBL strains. The combined treatment is synergistic, as it showed a fractional inhibitory concentration (FIC) index value of 0.15. CONCLUSIONS: The aPDI effectively inhibits clinical isolates of K. pneumoniae, including the riskier strains of ESBL-producing bacteria and the K2+, ybtS+, and allS+ genotype. The aPDI with PSIR-3 is synergistic with Cfx.

The mode of action of the PSIR-3 photosensitizer in the photodynamic inactivation of Klebsiella pneumoniae is by the production of type II ROS which activate RpoE-regulated extracytoplasmic factors.

BACKGROUND: Due to increased bacterial multi-drug resistance (MDR), there is an antibiotic depletion to treat infectious diseases. Consequently, other promising options have emerged, such as the antimicrobial photodynamic inactivation therapy (aPDI) based on photosensitizer (PS) compounds to produce light-activated local oxidative stress (photooxidative stress). However, there are scarce studies regarding the mode of action of PS compounds to induce photooxidative stress on pathogenic γ-proteobacteria such as MDR-Klebsiella pneumoniae. METHODOLOGY: The mode of action exerted by the cationic Ir(III)-based PS (PSIR-3) to inhibit the growth of K. pneumoniae was analyzed. RT-qPCR determined the transcriptional response induced by PSIR-3 on bacteria treated with aPDI. The expression levels of genes associated with a bacterial oxidative response, such as oxyR and sodA, and the extracytoplasmic, regulators rpoE and hfq were determined. Also, were determined the transcriptional response of the extracytoplasmic factors mrkD, acrB, magA, and rmpA. RESULTS: At 17 µW/cm2 photon flux and 4 µg/mL of the PSIR-3 compound, the K. pneumoniae growth was inhibited in 3 log10. Compared with untreated bacteria, the transcriptional response induced by PSIR-3 occurs via the extracytoplasmic sigma factor rpoE and hfq. In contrast, no participation in the oxyR pathway or induction of the sodA gene was observed. This response was accompanied by the upregulation of the extracytoplasmic virulence factors mrkD, magA, and rmpA. CONCLUSIONS: PDI aPDI produced by PSIR-3 kills K. pneumoniae and may induce damage to the bacterial envelope. The bacterium tries to avoid this injury by activation of extracytoplasmic factors mediated through the rpoE regulon.

Synergistic effect of combined imipenem and photodynamic treatment with the cationic Ir(III) complexes to polypyridine ligand on carbapenem-resistant Klebsiella pneumoniae.

BACKGROUND: Carbapenemase-producing strains of Klebsiella pneumoniae (KPC+) are one of the multi-drug resistant bacteria with the highest risk for human health. The colistin is the only antibiotic option against KPC+; however, due to its emerging resistance, therapies such as antimicrobial photodynamic inactivation (aPDI), are needed. APDI uses photosensitizer compounds (PS) to produce light-activated local oxidative stress (photooxidative stress). Within the PSs variety, cationic PSs are thought to interact closely with the bacterial envelope producing an increased cytotoxic effect. METHODOLOGY: The Ir(III)-based cationic compounds, PSIR-3, and PSIR-4 were tested on aPDI and compared to a positive control of Ru(II)-based PS. The PSIR-3 and PSIR-4 abilities to inhibit the growth of KPC+ and KPC- bacteria were evaluated, under 17 µW/cm2 photon flux. Also, the cytotoxicity of the PSs in eukaryotic cells was determined by MTS and trypan blue exclusion assays. RESULTS: After light-activation, only the PSIR-3 compound inhibited 3 log10 (> 99.9 %) bacterial growth in a minimum dose of 4 µg/mL with the lethality of 30 min of light exposure. Outstandingly, the compound PSIR-3 showed a synergistic effect with imipenem, significantly increasing the bacterial inhibition of KPC+ to 6 log10, which was not observed in the control compound. In normal immortalized gastric cell line GES-1, the compound PSIR-3 showed no significant cytotoxicity, although increased cytotoxicity under light-activation was observed on gastric cancer-derived cells AGS. CONCLUSION: The PSIR-3 compound produces an efficient aPDI, killing K. pneumoniae KPC+- strains, and increasing its susceptibility in conjunction with imipenem, exhibiting low cytotoxicity to normal eukaryotic cells.

Photodynamic treatment with cationic Ir(III) complexes induces a synergistic antimicrobial effect with imipenem over carbapenem-resistant Klebsiella pneumoniae.

BACKGROUND: Bacteria prevalent in the hospital environment have developed multi-drug resistance (MDR), such as the carbapenemase-producing Klebsiella pneumoniae (KPC+). Photodynamic therapy (PDT), which uses light-activated photosensitizer compounds (PSs), has emerged as an alternative to antibiotics. Cationic-PSs have a better bactericidal effect by interacting more closely with the bacterial envelope. METHODS: Two PSs based on cationic Ir (III) compounds (PSIR-1 and PSIR-2) were studied in photodynamic therapy against KPC+ and KPC- bacteria, and their PDT activities were compared with a cationic Ru(II) control compound (PS -Ru). RESULTS: Similar to the behavior of PS-Ru control, the cytotoxicity of PSIR-1 and 2, showing a bacterial inhibition growth of more than 3log10 (>99.9 % inactivation), at light fluency of 17 µW/cm2. The minimal dose to accomplish the inhibition in 3log10 was determined for PSIR-1 and PSIR-2 at 4 and 2 µg/mL, respectively and the lethality was 30 min of light exposure for both compounds. Notably, the PSIR-1 and 2 compounds showed a synergistic effect with imipenem by significantly increasing (up to 6 log10) the photodynamic bactericidal effect for KPC+ strains. This synergy is specific for PSIR-1 and 2 compounds, since it was not observed with the PS-Ru control. On normal gastric cells GES-1, both PSIR-1 and 2 showed significant cytotoxicity; however, the highest cytotoxicity was found in gastric tumor cells (AGS). CONCLUSION: The compounds PSIR-1 and 2 are bactericidal photosensitizers and represent a promising alternative for complementing the treatment of infections by MDR bacteria since they should not be toxic in the dark.

Controlled dispersion of ZnO nanoparticles produced by basic precipitation in solvothermal processes.

Zinc oxide nanoparticles were successfully synthesized under precipitation processes, using ZnSO4·7H2O as a Zn2+ precursor and K2CO3 used as a basic source, and hydrozincite was obtained as an intermediary, which was treated under two procedures; first procedure involved multiple stages to get final precipitated with NaOH, and in the second procedure the hydrozincite was straightforwardly dried at 220 °C. By both processes ZnO structures were obtained, which were turned into nanoparticles by a solvothermal treatment, for four hours in ethylene glycol at 200 °C. The final products for the first procedure was conglomerate of spherical nanoparticles with sizes ranged between 5-10 nm and dispersed ellipsoidal nanoparticles for the second procedure. Apart off the two procedures mentioned above, another synthesis was carried out with the same Zn2+ precursor but now using NaOH, and the solvothermal treatment produced ZnO mixed micro-structures which under ultrasonic cavitation disaggregated on mesoporous ZnO nanoplates of hexagonal shapes with nanopore sizes of approximately 0.35 nm. All ZnOs synthesized were structurally characterized with XRD, TEM and FT-IR techniques, and electronically with UV-Vis absorption and diffuse reflectance spectroscopies.

Correction: A comparative study of Ir(iii) complexes with pyrazino[2,3-f][1,10]phenanthroline and pyrazino[2,3-f][4,7]phenanthroline ligands in light-emitting electrochemical cells (LECs).

Correction for 'A comparative study of Ir(iii) complexes with pyrazino[2,3-f][1,10]phenanthroline and pyrazino[2,3-f][4,7]phenanthroline ligands in light-emitting electrochemical cells (LECs)' by Iván González et al., Dalton Trans., 2015, 44, 14771-14781.

About the electronic and photophysical properties of iridium(III)-pyrazino[2,3-f][1,10]-phenanthroline based complexes for use in electroluminescent devices.

A family of cyclometalated Ir(III) complexes was studied through quantum chemistry calculations to get insights into their applicability in light electrochemical cells (LECs). The complexes are described as [Ir(R-C^N)2(ppl)](+), where ppl is the pyrazino[2,3-f][1,10]-phenanthroline ancillary ligand. The modification of the HOMO energy in all the complexes was achieved by means of different R-C^N cyclometalating ligands, with R-ppy (phenylpyridine), R-pyz (1-phenylpyrazole) or R-pypy (2,3'-bipyridine); in addition, inductive effects were taken into account by substitution with the R groups (R = H, F or CF3). Then, compounds with HOMO-LUMO energy gaps from 2.76 to 3.54 eV were obtained, in addition to emission energies in the range of 438 to 597 nm. The emission deactivation pathways confirm the presence of metal-to-ligand transitions in all the complexes, which allow the strong spin-orbit coupling effects, and then improving the luminescence performance. However, the coupling with ligand and metal centered excited states was observed for the blue-shifted emitters, which could result in a decrease of the luminescence efficiencies. Furthermore, ionization potentials, electron affinities and reorganization energies (for holes and electrons) were obtained to account for the injection and transport properties of all the complexes in electroluminescent devices.

Electrocatalytic Transformation of Carbon Dioxide into Low Carbon Compounds on Conducting Polymers Derived from Multimetallic Porphyrins.

The electrochemical reduction of carbon dioxide is studied herein by using conducting polymers based on metallotetraruthenated porphyrins (MTRPs). The polymers on glassy carbon electrodes were obtained by electropolymerization processes of the monomeric MTRP. The linear sweep voltammetry technique resulted in polymeric films that showed electrocatalytic activity toward carbon dioxide reduction with an onset potential of -0.70 V. The reduction products obtained were hydrogen, formic acid, formaldehyde, and methanol, with a tendency for a high production of methanol with a maximum value of turnover frequency equal to 15.07 when using a zinc(II) polymeric surface. Studies of the morphology (AFM) and electrochemical impedance spectroscopy results provide an adequate background to explain that the electrochemical reduction is governed by the roughness of the polymer, for which the possible mechanism involves a series of one-electron reduction reactions.

A comparative study of Ir(III) complexes with pyrazino[2,3-f][1,10]phenanthroline and pyrazino[2,3-f][4,7]phenanthroline ligands in light-emitting electrochemical cells (LECs).

We report the comparative study of the electrochemical and photoluminescent properties of two Ir(iii) complexes described as [Ir(F2ppy)2(N^N)][PF6], where the F2ppy ligand is 2-(2,4-difluorophenyl)pyridine and the N^N ligands are pyrazino[2,3-f][1,10]phenanthroline (ppl) and pyrazino[2,3-f][4,7]phenanthroline (ppz). The complexes were used for the fabrication of light-emitting electrochemical cells (LECs). The structures of the complexes have been corroborated by X-ray crystallography. Theoretical calculations were performed to understand the photophysical behavior of the complexes. Both in solution and solid state, the photoluminescence spectra shows that emission is significantly red-shifted in the [Ir(F2ppy)2(ppz)][PF6] complex compared with the [Ir(F2ppy)2(ppl)][PF6] complex. Besides, the [Ir(F2ppy)2(ppl)][PF6] complex exhibits a higher quantum yield and a longer excited state lifetime than the [Ir(F2ppy)2(ppz)][PF6] complex; therefore, in the last case non-radiative decay is predominant due to the stabilization of LUMO orbital (energy gap law). In the fabrication of LEC devices with the [Ir(F2ppy)2(ppl)][PF6] complex, light emission was obtained with a maximum value of luminance equal to 177 cd m(-2), while in the case of the [Ir(F2ppy)2(ppz)][PF6] complex, no luminance was observed. According to the photophysical data, the performance in LEC devices could be explained by the different position of the nitrogens in the ppl and ppz structural isomers, electronically affecting the complex, and therefore its properties. In addition, from the crystallographic analysis it is possible to note that the [Ir(F2ppy)2(ppz)][PF6] complex shows enhanced intermolecular and intramolecular interactions compared with [Ir(F2ppy)2(ppl)][PF6], and consequently a higher ordering of the molecules in the complex with ppz ligand can be expected. This higher order could favour the quenching processes, and consequently enhance the non-radiative deactivation.

Effect of free rotation in polypyridinic ligands of Ru(II) complexes applied in light-emitting electrochemical cells.

In the present work we report the synthesis and the electrochemical, photoluminescent and electroluminescent properties of two new Ru(II) complexes described by the general formula [Ru(phen)2X](2+), where phen is 1,10-phenanthroline. The X ligand consists of a 2,2'-bipyridine (bpy) unit substituted with two phenyl rings connected to the bpy core through a saturated (Lhydro = 4,4'-diphenylethyl-2,2'-bipyridine) or a conjugated (LH = 4,4'-bis(α-styrene)-2,2'-bipyridine) carbon-carbon bridge. The photoluminescent spectra indicate that, both in solution and solid state, the complex bearing the aliphatic substitution bridges exhibits a higher quantum yield and a longer excited state lifetime than the fully conjugated complex. The new complexes were used in light-emitting electrochemical cells (LECs) showing red emission for the complex with the Lhydro ligand and no light emission for the complex incorporating the LH ligand. This and the photophysical properties make it plausible that for these complexes the degree of freedom increases with aliphatic substitution. As a consequence, the negative effect of the auto-quenching processes taking place in solid LEC devices due to the close molecular packing is limited. When compared with the archetype [Ru(phen)3](2+) complex, the complex with aliphatic substitution shows better performance in the device supporting the beneficial effect of the bulky substitution.