Shane M. Hickey

Synthetic mimetics of antimicrobial peptides (AMPs) typically rely on amine or guanidine groups to provide an overall cationic charge, often overlooking the metal-binding functionalities that influence AMP-membrane interactions. Here, we report three coumarin amphiphiles incorporating hydrophilic metal-binding headgroups and demonstrate that this design strategy yields improved potency and selectivity. All three compounds displayed strong antibacterial activity against methicillin-resistant S. aureus (MRSA), and a diethylenetriamine (DETA) derivative was also active against the Gram-negative bacteria, A. baumannii and E. coli. The compounds also showed moderate activity against MRSA biofilms, reducing the biomass of established MRSA biofilms by 40–50%. Mechanistic investigations revealed that the DETA and cyclen derivatives increased the outer-membrane permeability of E. coli and potentiated the activity of minocycline and rifampicin. All three amphiphiles also exhibited potent antifungal activity against C. neoformans, surpassing the activity of the clinical control fluconazole, with the DETA analogue also displaying activity against C. albicans. Collectively, these results suggest that incorporating metal-binding headgroups into amphiphilic scaffolds may engage a distinct mode of action compared to traditional small-molecule AMP mimetics, resulting in increased antimicrobial potency and selectivity over mammalian membranes.

Prostate cancer tissue usually involves either well formed glands, poorly formed glands or a combination of the two morphologies, which can be correlated with metabolic differences and tumor heterogeneity. This is particularly important for metastatic castration-resistant prostate cancer, where the heterogeneity and metabolic changes drive cancer progression and treatment refractory properties. Sortilin and syndecan-1 expression accurately define the two different morphologies in prostate cancer tissue, are critical to the process of metabolic regulation, and exhibit mechanistic/functional interactions during prostate cancer progression. As trans-membrane proteins that recycle from endocytic compartments to the cell surface, sortilin and syndecan-1 are attractive targets for therapeutic intervention that address the two major forms of prostate cancer. In this study, we describe an antibody-drug conjugate (ADC) strategy that utilizes monoclonal antibodies which bind to specific extracellular domains of these integral membrane proteins to elicit anticancer activity in prostate cancer cell lines. Anti-sortilin (clone 11H8) and anti-syndecan-1 (clone 6D11) monoclonal antibodies demonstrated high specificity for epitopes on the extracellular, N-terminal domains of these respective proteins and were effectively internalized into prostate cancer cell endocytic compartments. Monomethyl aurastatin E (MMAE)-conjugated ADCs exhibited low nanomolar cytotoxicity in LNCaP and PC-3 prostate cancer cells. Mechanistically, 11H8-MMAE and 6D11-MMAE triggered cytotoxicity and morphological alterations in androgen-sensitive and androgen-insensitive cells. However, the uptake of fluorescent labelled 11H8 and 6D11 antibodies appeared to be high, whereas the killing capacity of the MMAE-conjugated antibodies was less impressive, suggesting the need for further ADC development. These promising proof-of-concept ADCs are designed to exploit molecular and metabolic vulnerabilities in prostate cancer and may have utility for overcoming treatment resistance by simultaneously targeting different forms of the cancer.

Melanoma exhibits inherent heterogeneity and a high metastatic propensity, posing significant challenges for diagnosis, prognosis, and treatment. There are recognized problems with the visual detection of melanoma, such as amelanocytic lesions, which indicate that melanogenesis is downstream of the critical pathogenesis. The endosome–lysosome system regulates trafficking to control melanogenesis, and endosome function/signaling is directly impacted by common melanoma mutations. The endosomal–lysosomal system is also integrally involved in the regulation of fundamental cellular processes that are associated with other key hallmarks of this cancer. This traditional narrative review explores the relationship between altered endosomal–lysosomal biogenesis, aberrant melanogenesis, and oncogenic function in melanoma, including the potential effects on proliferation, invasion, and metastasis. Elucidating the molecular mechanisms underpinning the altered endosomal–lysosomal biology in melanoma is important as this has the potential to define new diagnostic and prognostic biomarkers to improve patient management.

A small series of cationic coumarin amphiphiles, designed to mimic antimicrobial peptides, eradicate MRSA biofilms and show promise as potential antibiofilm agents.

Neurobiological research relies heavily on imaging techniques, such as fluorescence microscopy, to understand neurological function and disease processes. However, the number and variety of fluorescent probes available for ex vivo tissue section imaging limits the advance of research in the field. In this review, we outline the current range of fluorescent probes that are available to researchers for ex vivo brain section imaging, including their physical and chemical characteristics, staining targets, and examples of discoveries for which they have been used. This review is organised into sections based on the biological target of the probe, including subcellular organelles, chemical species (e.g., labile metal ions), and pathological phenomenon (e.g., degenerating cells, aggregated proteins). We hope to inspire further development in this field, given the considerable benefits to be gained by the greater availability of suitably sensitive probes that have specificity for important brain tissue targets.

Neutral Re(I) morpholine complexes exhibiting long emission lifetimes, high photo- and pH stability and low cytotoxicity for imaging endosome-lysosome compartments.

Dysregulated production of hydrogen sulphide in the human body has been associated with various diseases including cancer, underlining the importance of accurate detection of this molecule. Here, we report the detection of hydrogen sulphide using fluorescence-emission enhancement of two 1,8-naphthalimide fluorescent probes with an azide moiety in position 4. One probe, serving as a control, featured a methoxyethyl moiety through the imide to evaluate its effectiveness for hydrogen sulphide detection, while the other probe was modified with (3-aminopropyl)triethoxysilane (APTES) to enable direct covalent attachment to an optical fibre tip. We coated the optical fibre tip relatively homogeneously with the APTES-azide fluorophore, as confirmed via x-ray photoelectron spectroscopy (XPS). The absorption and fluorescence responses of the control fluorophore free in PBS were analysed using UV-Vis and fluorescence spectrophotometry, while the fluorescence emission of the APTES-azide fluorophore-coated optical fibres was examined using a simple, low-cost optical fibre-based setup. Both fluorescent probes exhibited a significant increase (more than double the initial value) in fluorescence emission upon the addition of HS⁻ when excited with 405 nm. However, the fluorescence enhancement of the coated optical fibres demonstrated a much faster response time of 2 min (time for the fluorescence intensity to reach 90% of its maximum value) compared to the control fluorophore in solution (30 min). Additionally, the temporal evolution of fluorescence intensity of the fluorophore coated on the optical fibre was studied at two pH values (7.4 and 6.4), demonstrating a reasonable overlap and confirming the compound pH insensitivity within this range. The promising results from this study indicate the potential for developing an optical fibre-based sensing system for HS⁻ detection using the synthesised fluorophore, which could have significant applications in health monitoring and disease detection.

Background: Early diagnosis is the key to improving outcomes for patients with melanoma, and this requires a standardized histological assessment approach. The objective of this survey was to understand the challenges faced by clinicians when assessing melanoma cases, and to provide a perspective for future studies. Methods: Between April 2022 and February 2023, national and international dermatologists, pathologists, general practitioners, and laboratory managers were invited to participate in a six-question online survey. The data from the survey were assessed using descriptive statistics and qualitative responses. Results: A total of 54 responses were received, with a 51.4% (n = 28) full completion rate. Of the respondents, 96.4% reported ambiguity in their monthly melanoma diagnosis, and 82.1% routinely requested immunohistochemistry (IHC) testing to confirm diagnosis. SOX10 was the most frequently requested marker, and most respondents preferred multiple markers over a single marker. Diagnostic and prognostic tests, as well as therapeutic options and patient management, were all identified as important areas for future research. Conclusions: The respondents indicated that the use of multiple IHC markers is essential to facilitate diagnostic accuracy in melanoma assessment. Survey responses indicate there is an urgent need to develop new biomarkers for clinical decision making at multiple critical intervention points.