RESUMEN
Uropathogenic Escherichia coli (UPECs) is a leading cause for urinary tract infections (UTI), accounting for 70-90 % of community or hospital-acquired bacterial infections owing to high recurrence, imprecision in diagnosis and management, and increasing prevalence of antibiotic resistance. Current methods for clinical UPECs detection still rely on labor-intensive urine cultures that impede rapid and accurate diagnosis for timely UTI therapeutic management. Herein, we developed a first-in-class near-infrared (NIR) UPECs fluorescent probe (NO-AH) capable of specifically targeting UPECs through its collaborative response to bacterial enzymes, enabling locoregional imaging of UTIs both in vitro and in vivo. Our NO-AH probe incorporates a dual protease activatable moiety, which first reacts with OmpT, an endopeptidase abundantly present on the outer membrane of UPECs, releasing an intermediate amino acid residue conjugated with a NIR hemicyanine fluorophore. Such liberated fragment would be subsequently recognized by aminopeptidase (APN) within the periplasm of UPECs, activating localized fluorescence for precise imaging of UTIs in complex living environments. The peculiar specificity and selectivity of NO-AH, facilitated by the collaborative action of bacterial enzymes, features a timely and accurate identification of UPECs-infected UTIs, which could overcome misdiagnosis in conventional urine tests, thus opening new avenues towards reliable UTI diagnosis and personalized antimicrobial therapy management.
Asunto(s)
Colorantes Fluorescentes , Infecciones Urinarias , Infecciones Urinarias/microbiología , Infecciones Urinarias/diagnóstico , Colorantes Fluorescentes/química , Escherichia coli Uropatógena/enzimología , Animales , Ratones , Imagen Óptica , Humanos , Sondas Moleculares/químicaRESUMEN
Polycyclic aromatic molecules are promising functional materials for a wide range of applications, especially in organic electronics. However, their largely hydrophobic nature has impeded further applications. As such, imparting high solubility/hydrophilicity to polycyclic aromatic molecules leads to a breakthrough in this research field. Herein, we report the synthesis of diazapentabenzocorannulenium, a cationic nitrogen-embedded buckybowl bearing a central imidazolium core, by a bottom-up strategy from polycyclic aromatic azomethine ylide. X-ray crystallography analyses have revealed a bowl-shaped molecular structure that is capable of forming charge-segregated one-dimensional columns by bowl-in-bowl packing. In addition to its fluorescence capabilities and high dispersibility in water, the molecule was found to selectively localize in the mitochondria of various tumor cells, showing potential as viable mitochondria-selective fluorescent probes.
RESUMEN
Real-time monitoring of the evolution of bacterial infection-associated multiple radical species is critical to accurately profile the pathogenesis and host-defense mechanisms. Here, we present a unique dual wavelength near-infrared (NIR) cyanine-dyad molecular probe (HCy5-Cy7) for simultaneous monitoring of reactive oxygen and nitrogen species (RONS) variations both inâ vitro and inâ vivo. HCy5-Cy7 specifically turns on its fluorescence at 660â nm via superoxide or hydroxyl radical (O2.- , . OH)-mediated oxidation of reduced HCy5 moiety to Cy5, while peroxynitrite or hypochlorous species (ONOO- , ClO- )-induced Cy7 structural degradation causes the emission turn-off at 800â nm. Such multispectral but reverse signal responses allow multiplex manifestation of inâ situ oxidative and nitrosative stress events during the pathogenic and defensive processes in both bacteria-infected macrophage cells and living mice. Most importantly, this study may also provide new perspectives for understanding the bacterial pathogenesis and advancing the precision medicine against infectious diseases.
Asunto(s)
Infecciones Bacterianas/diagnóstico por imagen , Carbocianinas/química , Colorantes/química , Animales , Ratones , Células RAW 264.7 , Especies de Nitrógeno Reactivo/análisis , Especies Reactivas de Oxígeno/análisisRESUMEN
The emergence of multi-drug resistant bacteria strains has been an uphill battle in modern healthcare worldwide, due to the increasing difficulty of killing them. The evolving pathogenicity of bacteria has led to researchers searching for more effective antimicrobial therapeutics to successfully eliminate them without undesirable consequences to the human body. In recent years, antimicrobial photodynamic therapy (APDT), an obsolete technique for cancer treatments, has been reported to eradicate bacteria and biofilm-related infections. The principle of antimicrobial photodynamic therapy solely relies on the photosensitizers (PSs) generating reactive oxygen species, in the presence of oxygen and light, to destroy pathogens. Thus, it can target a broad spectrum of microorganisms, owing to the indirect interaction between PSs and the bacteria, resulting in the less likelihood for the development of drug resistant bacteria strains. This review will focus on the recent progress of APDT in the last five years and some future perspectives of APDT. The mechanism of APDT against bacteria and biofilms, various PSs used for APDT, and some common multidrug-resistant bacteria strains will be briefly introduced. The reported inâ vivo applications of APDT in the several types of bacterial infections that includes periodontitis, wound infections, keratitis, endophthalmitis and tuberculosis in the last five years will be summarized in detail.
Asunto(s)
Antiinfecciosos , Fotoquimioterapia , Humanos , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Antiinfecciosos/farmacología , Antiinfecciosos/uso terapéutico , Bacterias , BiopelículasRESUMEN
An unconventional environment-responsive molecular crowding via specific binding between small molecule peptide inhibitor derivatives and an overexpressed tumour enzyme has been developed. Assemblies of such short peptides selectively localize on tumour surfaces and exhibited unique functions in disrupting hyperactivated glucose uptake, providing novel insights towards strategic tumour treatment.
Asunto(s)
Glucosa/química , Péptidos/química , Línea Celular Tumoral , Ingestión de Alimentos , Furina/metabolismo , Regulación de la Expresión Génica , Glucosa/metabolismo , Humanos , Hidrogeles/química , Péptidos/metabolismo , Microambiente TumoralRESUMEN
In situ self-assembly has attracted increasing research interest for applications in imaging and therapy in recent years. Particularly for protease-activated developments, inspiration is drawn from the innate specificity of their catalytic activities, rapid discovery of the various roles they play in the proliferation of certain diseases, and inherent susceptibility of small molecule peptide conjugates to proteolytic digestion in vivo. The overexpression of a disease-related protease of interest can be exploited as an endogenous stimulus for site-specific self-assembly to largely amplify a molecular event happening at the cellular level. This holds great potential for applications in early stage disease detection, long-term disease monitoring, and sustained therapeutic effects. This review summarizes the recent developments in protease-activated self-assemblies for imaging and therapeutic applications toward the manifestation of tumors, bacterial infections, neurodegenerative disorders, and wound recovery.
Asunto(s)
Materiales Biocompatibles/farmacología , Neoplasias/tratamiento farmacológico , Péptido Hidrolasas/metabolismo , Péptidos/farmacología , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/metabolismo , Materiales Biocompatibles/química , Materiales Biocompatibles/metabolismo , Humanos , Ensayo de Materiales , Neoplasias/metabolismo , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/metabolismo , Tamaño de la Partícula , Péptido Hidrolasas/química , Péptidos/química , Péptidos/metabolismo , Cicatrización de Heridas/efectos de los fármacosRESUMEN
Triphenylphosphonium (TPP+) moieties are commonly conjugated to drug molecules to confer mitochondrial selectivity due to their positive charge and high lipophilicity. Although optimisation of lipophilicity can be achieved by modifying the length of the alkyl linkers between the TPP+ moiety and the drug molecule, it is not always possible. While methylation of the TPP+ moiety is a viable alternative to increase lipophilicity and mitochondrial accumulation, there are no studies comparing these two separate modular approaches. Thus, we have systematically designed, synthesised and tested a range of TPP+ molecules with varying alkyl chain lengths and degree of aryl methylation to compare the two modular methodologies for modulating lipophilicity. The ability of aryl/alkyl modified TPP+ to deliver cargo to the mitochondria was also evaluated by confocal imaging with a TPP+-conjugated fluorescein-based fluorophore. Furthermore, we have employed molecular dynamics simulations to understand the translocation of these molecules through biological membrane model systems. These results provide further insights into the thermodynamics of this process and the effect of alkyl and aryl modular modifications.