Environmentally sensitive photosensitizers enable targeted photodynamic ablation of Gram-positive antibiotic resistant bacteria

Bacterial infections remain among the biggest challenges to human health, leading to high antibiotic usage, morbidity, hospitalizations, and accounting for approximately 8 million deaths worldwide every year. The overuse of antibiotics and paucity of antimicrobial innovation has led to antimicrobial resistant pathogens that threaten to reverse key advances of modern medicine. Photodynamic therapeutics can kill bacteria but there are few agents that can ablate pathogens with minimal off-target effects.Methods: We describe nitrobenzoselenadiazoles as some of the first environmentally sensitive organic photosensitizers, and their adaptation to produce theranostics with optical detection and light-controlled antimicrobial activity. We combined nitrobenzoselenadiazoles with bacteria-targeting moieties (i.e., glucose-6-phosphate, amoxicillin, vancomycin) producing environmentally sensitive photodynamic agents.Results: The labelled vancomycin conjugate was able to both visualize and eradicate multidrug resistant Gram-positive ESKAPE pathogens at nanomolar concentrations, including clinical isolates and those that form biofilms.Conclusion: Nitrobenzoselenadiazole conjugates are easily synthesized and display strong environment dependent ROS production. Due to their small size and non-invasive character, they unobtrusively label antimicrobial targeting moieties. We envisage that the simplicity and modularity of this chemical strategy will accelerate the rational design of new antimicrobial therapies for refractory bacterial infections

Enzyme-Activatable Near-Infrared Hemicyanines as Modular Scaffolds for in vivo Photodynamic Therapy

Photodynamic therapy is an anti-cancer treatment that requires illumination of photosensitizers to induce local cell death. Current near-infrared organic photosensitizers are built from large and non-modular structures that cannot be tuned to improve safety and minimize off-target toxicity. This work describes a novel chemical platform to generate enzyme-activatable near-infrared photosensitizers. We optimized the Se-bridged hemicyanine scaffold to include caging groups and biocompatible moieties, and generated cathepsin-triggered photosensitizers for effective ablation of human glioblastoma cells. Furthermore, we demonstrated that enzyme-activatable Se-bridged hemicyanines are effective photosensitizers for the safe ablation of microtumors in vivo, creating new avenues in the chemical design of targeted anti-cancer photodynamic therapy agents.</p

Photosensitizer-Amplified Antimicrobial Materials for Broad-spectrum Ablation of Resistant Pathogens in Ocular Infections

The emergence of multidrug resistant (MDR) pathogens and the scarcity of new potent antibiotics and antifungals are one of the biggest threats to human health. Antimicrobial photodynamic therapy (aPDT) combines light and photosensitizers to kill drug-resistant pathogens; however, there are limited materials that can effectively ablate different classes of infective pathogens. In the present work, a new class of benzodiazole-paired materials is designed as highly potent PDT agents with broad-spectrum antimicrobial activity upon illumination with nontoxic light. The results mechanistically demonstrate that the energy transfer and electron transfer between nonphotosensitive and photosensitive benzodiazole moieties embedded within pathogen-binding peptide sequences result in increased singlet oxygen generation and enhanced phototoxicity. Chemical optimization renders PEP3 as a novel PDT agent with remarkable activity against MDR bacteria and fungi as well as pathogens at different stages of development (e.g., biofilms, spores, and fungal hyphae), which also prove effective in an ex vivo porcine model of microbial keratitis. The chemical modularity of this strategy and its general compatibility with peptide-based targeting agents will accelerate the design of highly photosensitive materials for antimicrobial PDT.</p

Solvent-driven chirality for luminescent self- assembled structures: experiments and theory

We describe, for a single platinum complex bearing a dipeptide moiety, a solvent-driven interconversion from twisted to straight micrometric assembled structures with different chirality. The photophysical and morphological properties of the aggregates have been investigated as well as the role of the media and concentration. A real-time visualization of the solvent-driven interconversion processes has been achieved by confocal microscopy. Finally, atomistic and coarse-grained simulations, providing results consistent with the experimental observations, allow to obtain a molecular-level insight into the interesting solvent-responsive behavior of this system

Rational Design and Synthesis of Large Stokes Shift 2,6-Sulphur-Disubstituted BODIPYs for Cell Imaging

Five new disubstituted 2,6-thioaryl-BODIPY dyes were synthesized via selective aromatic electrophilic substitution from commercially available thiophenols. The analysis of the photophysical properties via absorption and emission spectroscopy showed unusually large Stokes shifts for BODIPY fluorophores (70&ndash;100 nm), which makes them suitable probes for bioimaging. Selected compounds were evaluated for labelling primary immune cells as well as different cancer cell lines using confocal fluorescence microscopy

First Step Towards a DevilÏs Staircase in Spin-Crossover Materials

[EN] The unprecedented bimetallic 2D coordination polymer {Fe[(Hg(SCN)3)2](4,4’-bipy)2}n exhibits a thermal high-spin (HS)$low-spin (LS) staircase-like conversion characterized by a multi-step dependence of the HS molar fraction gHS. Between the fully HS (gHS = 1) and LS (gHS = 0) phases, two steps associated with different ordering appear in terms of spin-state concentration waves (SSCW). On the gHS 0.5 step, a periodic SSCW forms with a HS-LS-HS-LS sequence. On the gHS 0.34 step, the 4D superspace crystallography structural refinement reveals an aperiodic SSCW, with a HS-LS sequence incommensurate with the molecular lattice. The formation of these different long-range spatially ordered structures of LS and HS states during the multi-step spin-crossover is discussed within the framework of “DevilÏs staircase”-type transitions. Spatially modulated phases are known in various types of materials but are uniquely related to molecular HS/LS bistability in this case.This work was supported by the Spanish Ministerio de Economia y Competitividad (MINECO), FEDER (CTQ2013-46275-P), Unidad de Excelencia Maria de Maeztu MDM-2015-0538, the Generalitat Valenciana through PROMETEO/2012/049. L.P.L. and F.J.V.M. thank the Universidad de Valencia and a MINECO for a predoctoral (FPI) grant. D.Z. thanks the Natural Science Foundation of China and China Scholarship Council. This work was supported by the Institut Universitaire de France, the National Research Agency (ANR-13-BS04-0002), Rennes Metropole and CNRS (Post-Doc funding of E.T.). E.C. and J.A.R. would like to thank G. Chastanet for meditations on the Devil's staircase.Trzop, E.; Zhang, D.; Piñeiro López, L.; Valverde Muñoz, FJ.; Muñoz Roca, MDC.; Palatinus, L.; Guerin, L.... (2016). First Step Towards a DevilÏs Staircase in Spin-Crossover Materials. Angewandte Chemie International Edition. 55:8675-8679. https://doi.org/10.1002/anie.201602441S867586795

Iron(II) Spin Crossover Complexes with 4,4′-Dipyridylethyne—Crystal Structures and Spin Crossover with Hysteresis

Three new iron(II) 1D coordination polymers with cooperative spin crossover behavior showing thermal hysteresis loops were synthesized using N2O2 Schiff base-like equatorial ligands and 4,4′-dipyridylethyne as a bridging, rigid axial linker. One of those iron(II) 1D coordination polymers showed a 73 K wide hysteresis below room temperature, which, upon solvent loss, decreased to a still remarkable 30 K wide hysteresis. Single crystal X-ray structures of two iron(II) coordination polymers and T-dependent powder XRD patterns are discussed to obtain insight into the structure property relationship of those materials.</jats:p

Iron(II) Spin Crossover Complexes with 4,4′-Dipyridylethyne—Crystal Structures and Spin Crossover with Hysteresis

Three new iron(II) 1D coordination polymers with cooperative spin crossover behavior showing thermal hysteresis loops were synthesized using N2O2 Schiff base-like equatorial ligands and 4,4&prime;-dipyridylethyne as a bridging, rigid axial linker. One of those iron(II) 1D coordination polymers showed a 73 K wide hysteresis below room temperature, which, upon solvent loss, decreased to a still remarkable 30 K wide hysteresis. Single crystal X-ray structures of two iron(II) coordination polymers and T-dependent powder XRD patterns are discussed to obtain insight into the structure property relationship of those materials

Iron(II) Spin Crossover Polymers of Planar N2O2 Schiff Base Templates and 4,4’-bis(pyridyl)urea Bridges

Introduction:The synthesis of four new iron(II) coordination polymers [Fe(L1a)(bpua)] (1), [Fe(L1b)(bpua)](0.5bpua) (2), [Fe(L2a)(bpua)] (3), [Fe(L1b)(bpua)](yEtOH) (5) and one trinuclear complex [{Fe(L1a)(bpua)(MeOH)}2-µ{Fe(L1a)}](xMeOH) (4) with Schiff base-like N2O2coordinating equatorial ligands (L1a, L1b and L2a) and 4,4’-bis(pyridyl)urea (bpua) as bridging axial ligand is described.Materials and Methods:Single crystal X-ray structure elucidation of the trinuclear module4and of the coordination polymer5reveals the presence of HS-LS-HS chains and all-HS infinite 1-D strands, respectively. As anticipated the presence of the bridging urea supports the supramolecular concatenation within an extended hydrogen-bonding network. Magnetic measurements reveal spin crossover behavior for four of the five complexes (1–4) that is strongly solvent dependent.Results and Conclusion:Interestingly, in two cases, complete removal of the solvent from the crystal packing leads to wider thermal hysteresis loops.</jats:sec