A TCF-based fluorescent probe to determine nitroreductase (NTR) activity for a broad-spectrum of bacterial species.

A nitroreductase (NTR) responsive fluorescent probe with long wavelength fluorescence emission was used to determine the NTR activity of a selection of bacterial species under a range of different bacterial growth conditions ensuring applicability under multiple complex clinical environments, where sensitivity, reaction time, and the detection accuracy were suitable for planktonic cultures and biofilms.

Targeted photothermal release of antibiotics by a graphene nanoribbon-based supramolecular glycomaterial.

Here, we report the simple construction of a supramolecular glycomaterial for the targeted delivery of antibiotics to P. aeruginosa in a photothermally-controlled manner. A galactose-pyrene conjugate (Gal-pyr) was developed to self-assemble with graphene nanoribbon-based nanowires via π-π stacking to produce a supramolecular glycomaterial, which exhibits a 1250-fold enhanced binding avidity toward a galactose-selective lectin when compared to Gal-pyr. The as-prepared glycomaterial when loaded with an antibiotic that acts as an inhibitor of the bacterial folic acid biosynthetic pathway eradicated P. aeruginosa-derived biofilms under near-infrared light irradiation due to the strong photothermal effect of the nanowires accelerating antibiotic release.

TCF-based fluorescent probe for monitoring superoxide anion produced in bacteria under chloramphenicol- and heat-induced stress.

We report on a superoxide anion (O2˙-) responsive fluorescent probe called TCF-OTf. TCF-OTf is able to monitor O2˙- production when the bacterial species Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis are exposed to chloramphenicol and heat shock at 50 and 58 °C.

Metabolically Specific In Situ Fluorescent Visualization of Bacterial Infection on Wound Tissues.

The ability to effectively detect bacterial infection in human tissues is important for the timely treatment of the infection. However, traditional techniques fail to visualize bacterial species adhered to host cells in situ in a target-specific manner. Dihydropteroate synthase (DHPS) exclusively exists in bacterial species and metabolically converts p-aminobenzoic acid (PABA) to folic acid (FA). By targeting this bacterium-specific metabolism, we have developed a fluorescent imaging probe, PABA-DCM, based on the conjugation of PABA with a long-wavelength fluorophore, dicyanomethylene 4H-pyran (DCM). We confirmed that the probe can be used in the synthetic pathway of a broad spectrum of Gram-positive and negative bacteria, resulting in a significantly extended retention time in bacterial over mammalian cells. We validated that DHPS catalytically introduces a dihydropteridine group to the amino end of the PABA motif of PABA-DCM, and the resulting adduct leads to an increase in the FA levels of bacteria. We also constructed a hydrogel dressing containing PABA-DCM and graphene oxide (GO), termed PABA-DCM@GO, that achieves target-specific fluorescence visualization of bacterial infection on the wounded tissues of mice. Our research paves the way for the development of fluorescent imaging agents that target species-conserved metabolic pathways of microorganisms for the in situ monitoring of infections in human tissues.

Tuning the Solid- and Solution-State Fluorescence of the Iron-Chelator Deferasirox.

Deferasirox, an FDA-approved iron chelator, has gained increasing attention for use in anticancer and antimicrobial applications. Recent efforts by our group led to the identification of this core as an easy-to-visualize aggregation-induced emission platform, or AIEgen, that provides a therapeutic effect equivalent to deferasirox (J. Am. Chem. Soc. 2021, 143, 3, 1278-1283). However, the emission wavelength of the first-generation system overlapped with that of Syto9, a green emissive dye used to indicate live cells. Here, we report a library of deferasirox derivatives with various fluorescence emission profiles designed to overcome this limitation. We propose referring to systems that show promise as both therapeutic and optical imaging agents as "illuminoceuticals". The color differences between the derivatives were observable to the unaided eye (solid- and solution-state) and were in accord with the Commission Internationale de L'Eclairage (CIE) chromaticity diagram 1913. Each fluorescent derivative successfully imaged the respective spherical and rod shapes of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. They also displayed iron-dependent antibiotic activity. Three derivatives, ExNMe2 (3), ExTrisT (11), and ExDCM (13), display emission features that are sufficiently distinct so as to permit the multiplex (triplex) imaging of both MRSA and P. aeruginosa via stimulated emission depletion microscopy. The present deferasirox derivatives allowed for the construction of a multi-fluorophore sensor array. This array enabled the successful discrimination between Gram-positive/Gram-negative and drug-sensitive/drug-resistant bacteria. Antibiotic sensitivity and drug-resistant mutants from clinically isolated strains could also be identified and differentiated.

TCF-ALP: a fluorescent probe for the selective detection of Staphylococcus bacteria and application in "smart" wound dressings.

Alkaline phosphatase (ALP) is an important enzyme-based biomarker present in several bacterial species; however, it is currently undervalued as a strategy to detect pathogenic bacteria. Here, we explore our ALP-responsive colorimetric and fluorescent probe (TCF-ALP) for such applications. TCF-ALP displayed a colorimetric and fluorescence response towards Staphylococcus aureus (S. aureus), with a limit of detection of 3.7 × 106 CFU mL-1 after 24 h incubation. To our surprise, TCF-ALP proved selective towards Staphylococcus bacteria when compared with Enterococcus faecalis (E. faecalis), and Gram-negative P. aeruginosa and E. coli. Selectivity was also seen in clinically relevant S. aureus biofilms. Owing to the high prevalence and surface location of S. aureus in chronic wounds, TCF-ALP was subsequently encapsulated in polyvinyl alcohol (PVA)-based hydrogels as a proof-of-concept "smart" wound dressing. TCF-ALP hydrogels were capable of detecting S. aureus in planktonic and biofilm assays, and displayed a clear colour change from yellow to purple after 24 h incubation using ex vivo porcine skin models. Overall, TCF-ALP is a simple tool that requires no prior knowledge, training, or specialist equipment, and has the potential to overcome issues related to invasive swabbing and tissue biopsy methods. Thus, TCF-ALP could be used as a tool to monitor the early development of infection in a wound and allow for the rapid provision of appropriate treatment for Staphylococcal bacterial infections.

Correction: Fluorescent glycoconjugates and their applications.

Correction for 'Fluorescent glycoconjugates and their applications' by Baptiste Thomas et al., Chem. Soc. Rev., 2020, 49, 593-641, DOI: 10.1039/C8CS00118A.

Low-dimensional nanomaterials for antibacterial applications.

The excessive use of antibiotics has led to a rise in drug-resistant bacteria. These "superbugs" are continuously emerging and becoming increasingly harder to treat. As a result, new and effective treatment protocols that have minimal risks of generating drug-resistant bacteria are urgently required. Advanced nanomaterials are particularly promising due to their drug loading/releasing capabilities combined with their potential photodynamic/photothermal therapeutic properties. In this review, 0-dimensional, 1-dimensional, 2-dimensional, and 3-dimensional nanomaterial-based systems are comprehensively discussed for bacterial-based diagnostic and treatment applications. Since the use of these platforms as antibacterials is relatively new, this review will provide appropriate insight into their construction and applications. As such, we hope this review will inspire researchers to explore antibacterial-based nanomaterials with the aim of developing systems for clinical applications.

Deferasirox (ExJade): An FDA-Approved AIEgen Platform with Unique Photophysical Properties.

Deferasirox, ExJade, is an FDA-approved iron chelator used for the treatment of iron overload. In this work, we report several fluorescent deferasirox derivatives that display unique photophysical properties, i.e., aggregation-induced emission (AIE), excited state intramolecular proton transfer, charge transfer, and through-bond and through-space conjugation characteristics in aqueous media. Functionalization of the phenol units on the deferasirox scaffold afforded the fluorescent responsive pro-chelator ExPhos, which enabled the detection of the disease-based biomarker alkaline phosphatase (ALP). The diagnostic potential of these deferasirox derivatives was supported by bacterial biofilm studies.

A glycoconjugate-based gold nanoparticle approach for the targeted treatment of Pseudomonas aeruginosa biofilms.

In this study, "core-shell" gold nanoparticles (AuNPs) have been functionalised using a simple one-pot approach to form fucose-based glycoconjugate AuNPs (Fuc-AuNPs) and galactose-based glycoconjugate AuNPs (Gal-AuNPs), respectively. Owing to the selective carbohydrate-based recognition of the key virulence factors of P. aeruginosa, LecB (fucose-specific lectin)/LecA (galactose-specific lectin), Fuc-AuNPs and Gal-AuNPs-based imaging and therapeutic strategies were evaluated towards P. aeruginosa. Both Fuc-AuNPs and Gal-AuNPs were non-covalently loaded with the fluorophore dicyanomethylene 4H-pyran (DCM) to afford two highly selective fluorescence imaging agents for the visualisation of P. aeruginosa. The loading of Fuc-AuNPs and Gal-AuNPs with the known antibiotic Ceftazidime (CAZ) exhibited an enhanced therapeutic effect, illustrating the significance of this targeted drug delivery strategy. Exploiting the phototherapeutic properties of AuNPs, photoirradiation (600 nm) of Fuc-AuNP@CAZ/Gal-AuNP@CAZ provided both photothermal and photodynamic therapeutic (PTT/PDT) effects, which facilitated the release of CAZ. Fuc-AuNP@CAZ and Gal-AuNP@CAZ were shown to be effective photo/chemotherapeutics resulting in almost complete eradication of P. aeruginosa biofilms formed on clinically relevant surfaces (glass slides and steel surface).

Transition metal chelators, pro-chelators, and ionophores as small molecule cancer chemotherapeutic agents.

Cancer is among the leading causes of death worldwide. Although a number of new treatment options have been developed in recent years, there remains a need for improved chemotherapies. The primary challenges facing new cancer drugs include: (1) improving patient quality of life, (2) overcoming drug resistance and (3) lowering reoccurrence rates. Major drawbacks of current chemotherapeutics arise from poor selectivity towards cancer cells, dose limiting toxicities, compliance-reducing side effects, and an inability to address resistance mechanisms. Chemotherapeutics that fail to achieve complete eradication of the disease can also lead to relapse and promote treatment resistance. New strategies to overcome these drawbacks include the use of transition metal chelators and ionophores to alter selectively the concentrations of iron, copper, and zinc in cancer cells. A number of metal chelators have successfully demonstrated cytotoxicity and targeted activity against drug-resistant cancer cells; several have proved effective against cancer stem cells, a significant cause of tumour reoccurrence. However, problems with formulation and targeting have been noted. Recent efforts have thus focused on the design of pro-chelators, inactive versions of chelators that are designed to be activated in the tumour. This is an appealing strategy that may potentially increase efficacy towards cancer-resistant malignant cells. This Tutorial Review summarizes recent progress involving transition metal chelators, pro-chelators, and ionophores as potential cancer chemotherapeutics. We will focus on the reported agents that are able to coordinate iron, copper, and zinc.

Fluorescent glycoconjugates and their applications.

Glycoconjugates and their applications as lectin ligands in biology have been thoroughly investigated in the past decades. Meanwhile, the intrinsic properties of such multivalent molecules were limited essentially to their ability to bind to their receptors with high selectivity and/or avidity. The present review will focus on multivalent glycoconjugates displaying an additional capability such as fluorescence properties not only for applications toward imaging of cancer cells and detection of proteins or pathogens but also for drug delivery systems toward targeted cancer therapy. This review is a collection of research articles discussed in the context of the structural features of fluorescent glycoconjugates organized according to their fluorescent core scaffold and with their representative applications.