Synthesis of Di(thiophen-2-yl) Substituted Pyrene-Pyridine Conjugated Scaffold and DFT Insights: A Selective and Sensitive Colorimetric, and Ratiometric Fluorescent Sensor for Fe(III) Ions.

In this context, we used the multicomponent Chichibabin pyridine synthesis reaction to synthesize a novel di(thiophen-2-yl) substituted and pyrene-pyridine fluorescent molecular hybrid. The computational (DFT and TD-DFT) and experimental investigations were performed to understand the photophysical properties of the synthesized new structural scaffold. The synthesized ligand displays highly selective fluorescent sensing properties towards Fe3+ ions when compared to other competitive metal ions (Al3+, Ba2+, Ca2+, Cd2+, Co2+, Cr3+, Cu2+, Fe2+, Hg2+, Na+, Ni2+, Pb2+, Sr2+, Sn2+ and Zn2+). The photophysical properties studies reveal that the synthesized hybrid molecule has a binding constant of 2.30 × 103 M-1 with limit of detection (LOD) of 4.56 × 10-5 M (absorbance mode) and 5.84 × 10-5 M (emission mode) for Fe3+ ions. We believe that the synthesized pyrene-conjugated hybrid ligand can serve as a potential fluorescent chemosensor for the selective and specific detection of Fe3+ ions.

Hydrogel dressings with intrinsic antibiofilm and antioxidative dual functionalities accelerate infected diabetic wound healing.

Chronic wounds are often infected with biofilm bacteria and characterized by high oxidative stress. Current dressings that promote chronic wound healing either require additional processes such as photothermal irradiation or leave behind gross amounts of undesirable residues. We report a dual-functionality hydrogel dressing with intrinsic antibiofilm and antioxidative properties that are synergistic and low-leaching. The hydrogel is a crosslinked network with tethered antibacterial cationic polyimidazolium and antioxidative N-acetylcysteine. In a murine diabetic wound model, the hydrogel accelerates the closure of wounds infected with methicillin-resistant Staphylococcus aureus or carbapenem-resistant Pseudomonas aeruginosa biofilm. Furthermore, a three-dimensional ex vivo human skin equivalent model shows that N-acetylcysteine promotes the keratinocyte differentiation and accelerates the re-epithelialization process. Our hydrogel dressing can be made into different formats for the healing of both flat and deep infected chronic wounds without contamination of the wound or needing other modalities such as photothermal irradiation.

Multicomponent Reaction Based Tolyl-substituted and Pyrene-Pyridine Conjugated Isomeric Ratiometric Fluorescent Probes: A Comparative Investigation of Photophysical and Hg(II)-Sensing Behaviors.

Herein, the synthesis of pyrene conjugated 2,6-di-ortho-tolylpyridine and 2,6-di-para-tolylpyridine structural isomers were achieved efficiently through multicomponent Chichibabin pyridine synthesis reaction. The DFT, TD-DFT and experimental investigations were carried out to investigate the photophysical behaviors of the synthesized novel pyrene-pyridine based isomeric probes. Our studies revealed that, due to the continuous conjugation of the pyrene, pyridine and tolyl moieties, the dihedral angles of the trisubstituents on the central pyridine moiety significantly influences the photophysical properties of the synthesized novel pyrene based fluorescent probes. Further, we have comparatively investigated the sensing behaviors of the synthesized tolyl-substituted isomeric ratiometric fluorescent probes with metal ions, our studies reveals that both the ortho and para tolyl ratiometric fluorescent probes have distinct photoemissive properties in selectively sensing of Hg2+ ions. Our studies indicates that, the para-tolyl substituted isomer displays more red-shift in wavelength of emission band compared to its ortho isomer analogue during ratiometric fluorescent specific detection of Hg2+ ions.

Metabolic Labeling Mediated Targeting and Thermal Killing of Gram-Positive Bacteria by Self-Reporting Janus Magnetic Nanoparticles.

Nanoparticles have been widely used in detection and killing of bacteria; however, targeting bacteria is still challenging. Delicate design of nanoparticles is required for simultaneous targeting, detection, and therapeutic functions. Here the use of Au/MnFe2 O4 (Au/MFO) Janus nanoparticles to target Gram-positive bacteria via metabolic labeling is reported and realize integrated self-reporting and thermal killing of bacteria. In these nanoparticles, the Au component is functionalized with tetrazine to target trans-cyclooctene group anchored on bacterial cell wall by metabolic incorporation of d-amino acids, and the MFO part exhibits peroxidase activity, enabling self-reporting of bacteria before treatment. The spatial separation of targeting and reporting functions avoids the deterioration of catalytic activity after surface modification. Also important is that MFO facilitates magnetic separation and magnetic heating, leading to easy enrichment and magnetic thermal therapy of labeled bacteria. This method demonstrates that metabolic labeling with d-amino acids is a promising strategy to specifically target and kill Gram-positive bacteria.

Designer broad-spectrum polyimidazolium antibiotics.

For a myriad of different reasons most antimicrobial peptides (AMPs) have failed to reach clinical application. Different AMPs have different shortcomings including but not limited to toxicity issues, potency, limited spectrum of activity, or reduced activity in situ. We synthesized several cationic peptide mimics, main-chain cationic polyimidazoliums (PIMs), and discovered that, although select PIMs show little acute mammalian cell toxicity, they are potent broad-spectrum antibiotics with activity against even pan-antibiotic-resistant gram-positive and gram-negative bacteria, and mycobacteria. We selected PIM1, a particularly potent PIM, for mechanistic studies. Our experiments indicate PIM1 binds bacterial cell membranes by hydrophobic and electrostatic interactions, enters cells, and ultimately kills bacteria. Unlike cationic AMPs, such as colistin (CST), PIM1 does not permeabilize cell membranes. We show that a membrane electric potential is required for PIM1 activity. In laboratory evolution experiments with the gram-positive Staphylococcus aureus we obtained PIM1-resistant isolates most of which had menaquinone mutations, and we found that a site-directed menaquinone mutation also conferred PIM1 resistance. In similar experiments with the gram-negative pathogen Pseudomonas aeruginosa, PIM1-resistant mutants did not emerge. Although PIM1 was efficacious as a topical agent, intraperitoneal administration of PIM1 in mice showed some toxicity. We synthesized a PIM1 derivative, PIM1D, which is less hydrophobic than PIM1. PIM1D did not show evidence of toxicity but retained antibacterial activity and showed efficacy in murine sepsis infections. Our evidence indicates the PIMs have potential as candidates for development of new drugs for treatment of pan-resistant bacterial infections.

Multifunctional Glyco-Nanosheets to Eradicate Drug-Resistant Bacteria on Wounds.

Bacterial infection is becoming increasingly lethal with the emergence of antimicrobial resistance, and wounds plagued by such infection are notoriously difficult to heal. Here, the first use of galactose-black phosphorus nanosheets, (Gal-BP NSs) as a delivery platform for synergistic antibiotic (kanamycin, Kana) and photothermal treatments against the Gram-negative microbial strain, Pseudomonas aeruginosa PAO1 (PAO1) is reported. Gal-BP NSs@Kana can actively target PAO1 and release kanamycin into the bacterial cytoplasm upon near-infrared laser irradiation. This strategy kills most of the PAO1 through a simultaneous burst of intracellular kanamycin release and photothermal treatment. Comparable antibacterial activities of Gal-BP NSs@Kana are observed within in vivo mouse models at their wound sites. In addition, this platform accelerates wound healing from PAO1 infection via promotion of neoangiogenesis and collagen production at the wound sites. This work demonstrates the material properties of Gal-BP NS in fighting bacterial infections and in the treatment of wound healing.

A general approach to non-fullerene electron acceptors based on the corannulene motif.

Here, we show that oxidation of exo-cyclic sulfur atoms enhances the molecular reduction potential of non-planar polycyclic aromatic hydrocarbons and allows for a systematic bridging of the electron affinity gap between corannulene, a fragment of fullerene C60, and the prevalent fullerene-based electron acceptor phenyl-C61-butyric acid methyl ester (PCBM).

Raman-encoded, multivalent glycan-nanoconjugates for traceable specific binding and killing of bacteria.

Glycan recognition plays key roles in cell-cell and host-pathogen interactions, stimulating widespread interest in developing multivalent glycoconjugates with superior binding affinity for biological and medical uses. Here, we explore the use of Raman-encoded silver coated gold nanorods (GNRs) as scaffolds to form multivalent glycoconjugates. The plasmonic scaffolds afford high-loading of glycan density and their optical properties offer the possibilities of monitoring and quantitative analysis of glycan recognition. Using E. coli strains with tailored on/off of the FimH receptors, we have demonstrated that Raman-encoded GNRs not only allow for real-time imaging and spectroscopic detection of specific binding of the glycan-GNR conjugates with bacteria of interest, but also cause rapid eradication of the bacteria due to the efficient photothermal conversion of GNRs in the near-infrared spectral window. We envision that optically active plasmonic glycoconjugates hold great potential for screening multivalent glycan ligands for therapeutic and diagnostic applications.

Amphiphilic Corannulene Derivatives: Synthetic Access and Development of a Structure/Property Relationship in Thermoresponsive Buckybowl Amphiphiles.

Eight new derivatives of corannulene have been synthesized, characterized, and examined for their water solubility and thermally triggered assembly behavior. To achieve this, the hydrophobic corannulene core was attached to the hydrophilic polyethylene glycol arm(s). Here, the substitution pattern as well as the arm length was varied systematically. Furthermore, the hydrophobic/hydrophilic ratio was adjusted by incorporating a phenyl ring at the junction point of the two moieties. A properties study revealed that a proper balance among the number, length, and chemical nature of the arm was required to ensure water solubility and thermoresponsive character. Remarkably, the lower critical solution temperature could be modulated within the range of 30-50 °C simply through adjusting the molecular structure of the assembling building block. This work, therefore, demonstrates synthetic feasibility of a wide range of amphiphilic corannulene derivatives and opportunity for modulation of their thermoresponsive behavior.