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MGB-BP-3 is a potential first-in-class antibiotic, a Strathclyde Minor Groove Binder (S-MGB), that has successfully completed Phase IIa clinical trials for the treatment of

Quantitative drug imaging in live cells is a major challenge in drug discovery and development. Many drug screening techniques are performed in solution, and therefore do not consider the impact of the complex cellular environment in their result. As such, important features of drug-cell interactions may be overlooked. In this study, Raman microscopy is used as a powerful technique for semi-quantitative imaging of Strathclyde-minor groove binders (S-MGBs) in mammalian cells under biocompatible imaging conditions. Raman imaging determined the influence of the tail group of two novel minor groove binders (S-MGB-528 and S-MGB-529) in mammalian cell models. These novel S-MGBs contained alkyne moieties which enabled analysis in the cell-silent region of the Raman spectrum. The intracellular uptake concentration, distribution and mechanism were evaluated as a function of the p

This paper describes the design and synthesis of Strathclyde minor groove binders (S-MGBs) that have been truncated by the removal of a pyrrole ring in order to mimic the structure of the natural product, disgocidine. S-MGBs have been found to be active against many different organisms, however, selective antiparasitic activity is required. A panel of seven truncated S-MGBs was prepared and the activities examined against a number of clinically relevant organisms including several bacteria and parasites. The effect of the truncation strategy on S-MGB aggregation in aqueous environment was also investigated using 1H inspection and DOSY experiments. A lead compound, a truncated S-MGB, which possesses significant activity only against trypanosomes and Leishmania has been identified for further study and was also found to be less affected by aggregation compared to its full-length analogue., This paper describes the design and synthesis of Strathclyde minor groove binders (S-MGBs) that have been truncated by the removal of a pyrrole ring in order to mimic the structure of the natural product, disgocidine.

The neglected tropical disease leishmaniasis, caused by Leishmania spp., is becoming more problematic due to the emergence of drug-resistant strains. Therefore, new drugs to treat leishmaniasis, with novel mechanisms of action, are urgently required. Strathclyde minor groove binders (S-MGBs) are an emerging class of anti-infective agent that have been shown to have potent activity against various bacteria, viruses, fungi and parasites. Herein, it is shown that S-MGBs have potent activity against L. donovani, and that an N-oxide derivation of the tertiary amine tail of typical S-MGBs leads to selective anti-leishmanial activity. Additionally, using S-MGB-219, the N-oxide derivation is shown to retain strong binding to DNA as a 2:1 dimer. These findings support the further study of anti-leishmanial S-MGBs as novel therapeutics.

Gender issues, and specifically the lack of women in the physical sciences, has been a subject of intense debate for decades. The problem is so acute, that national initiatives have been developed to analyse and address the issues, with some success in STEM, particularly in higher education and also in industry. However, despite this progress, there is little understanding as to why women are less likely to study the chemical sciences in particular. In this research, a survey and interviews were used to find out why female A-level chemistry students choose, or do not choose, to study chemistry at higher education level. Two distinct phases were identified. Firstly, intelligence gathering to understand the location, content, entry requirements, and career options for potential course and institution combinations. Secondly, self-reflection to establish whether, knowing themselves, students feel as though they would be successful on a particular course at a particular institution. These findings align with research into gender imbalance in STEM and Higher Education more broadly, but go beyond this to broaden current debates with a focus on chemistry in particular.

Background Previously, we evaluated the intracellular mycobactericidal activity of the minor groove binder, S-MGB-364 against the clinical Mycobacterium tuberculosis (Mtb) strain HN878 in macrophages. Objectives To assess the mycobactericidal activity of S-MGB-364 in Mtb-infected mice. Further, we investigated a plausible DNA binding mechanism of action of S-MGB-364. Methods The anti-TB and host immune effects of intranasal S-MGB-364 or S-MGB-364 encapsulated in non-ionic surfactant vesicles (NIV) were assessed in Mtb-infected mice by cfu enumeration, ELISA, histology, and flow cytometry. DNA binding was examined using native mass spectrometry and UV-vis thermal melt determination. S-MGB interference with DNA-centric biological events was assessed using a representative panel of Mtb and human topoisomerase I, and gyrase assays. Results S-MGB-364 bound strongly to DNA as a dimer, significantly increasing the stability of the DNA:S-MGB complex compared with DNA alone. Moreover, S-MGB-364 inhibited the relaxation of Mtb topoisomerase I but not the human form. In macrophages, S-MGB-364 or S-MGB-364-NIV did not cause DNA damage as shown by the low γ-H2AX expression. Importantly, in the lungs, the intranasal administration of S-MGB-364 or S-MGB-364-NIV formulation in Mtb-infected mice was non-toxic and resulted in a ∼1 log cfu reduction in mycobacterial burden, reduced the expression of proinflammatory cytokines/chemokines, altered immune cell recruitment, and importantly reduced recruitment of neutrophils. Conclusions Together, these data provide proof of concept for S-MGBs as novel anti-TB therapeutics in vivo.

For many years, a key driver for Higher Education Institutions (HEIs) has been ensuring that students are prepared for employment post-graduation. This has often resulted in HEIs providing specific modules of study focussing on employability and soft skills. The existing research literature presents a variety of strategies for embedding employability within curricula, often focusing on frameworks to review the provision of employability opportunities within a degree programme. The authors have previously investigated an employability module within an Undergraduate Chemistry Programme at their UK HEI, particularly focusing on students’ perceptions–these coalesced around the themes of personal progression, relevance of the module and interactions. However, before using these findings to further develop the module, it was deemed necessary to investigate the module in a different context. This study investigates the employability module in an Australian HEI and its delivery to undergraduate and postgraduate students from a range of different disciplines. Free text comments from questionnaires answered by 85 participants were subjected to thematic analysis in order to understand students’ perceptions of the module in this new context. The new thematic map was compared to that from the original study to reveal several key similarities and differences between students’ perceptions. However, the most important finding is thast employability modules should be tailored to a specific cohort to ensure they are aligned with their needs. This suggests that Central University employability module providers should work closely with individual departments to maximise the impact of these for students.

Traditional cytotoxic agents which act through a DNA-alkylating mechanism are relatively non-specific, resulting in a small therapeutic window and thus limiting their effectiveness. In this study, we evaluate a panel of 24 non-alkylating Strathclyde Minor Groove Binders (S-MGBs), including 14 novel compounds, for in vitro anti-cancer activity against a human colon carcinoma cell line, a cisplatin-sensitive ovarian cancer cell line and a cisplatin-resistant ovarian cancer cell line. A human non-cancerous retinal epithelial cell line was used to measure selectivity of any response. We have identified several S-MGBs with activities comparable to cis-platin and carboplatin, but with better in vitro selectivity indices, particularly S-MGB-4, S-MGB-74 and S-MGB-317. Moreover, a comparison of the cis-platin resistant and cis-platin sensitive ovarian cancer cell lines reveals that our S-MGBs do not show cross resistance with cisplatin or carboplatin and that they likely have a different mechanism of action. Finally, we present an initial investigation into the mechanism of action of one compound from this class, S-MGB-4, demonstrating that neither DNA double strand breaks nor the DNA damage stress sensor protein p53 are induced. This indicates that our S-MGBs are unlikely to act through an alkylating or DNA damage response mechanism.

School pupils often perceive STEM subjects to be challenging; thus, in this project, an interactive, nationwide STEM investigation was designed to stimulate their interest. The “Soils in Scottish Schools” project provided teachers with a flexible package of resources to allow them to enhance the profile and understanding of soil science of their pupils. This package included presentations, experimental procedures, activities, and monthly newsletters which could be adapted to the particular learning environment of their pupils. In the focal point of the project, teachers were supported to encourage their pupils to collect samples from their school ground which were then analyzed for copper, lead, and zinc levels. This year-long project also afforded teachers with the opportunity to develop the pupils’ investigative skills through engagement with experiments in their own classrooms where they could engage with real data.

Objectives: The slow development of major advances in drug discovery for the treatment of\ud Mycobacterium tuberculosis (Mtb) infection have led to a compelling need for evaluation of\ud more effective drug therapies against tuberculosis. New classes of drugs are constantly being evaluated for anti-mycobacterial activity with currently a very limited number of new drugs approved for TB treatment. Minor Groove Binders (MGBs) have previously revealed promising anti-microbial activity against various infectious agents; however have not yet been screened against Mtb. \ud Methods: Mycobactericidal activity of MGB compounds against Mtb was determined using H37Rv-GFP microplate assay. MGB hits were screened for their intracellular mycobactericidal efficacy against clinical Beijing Mtb strain HN878 in bone marrow-derived\ud macrophages using standard colony-forming unit counting. Cell viability was assessed by\ud CellTiter-Blue assays. Selected MGB were encapsulated into non-ionic surfactant vesicles\ud (NIVs) for drug delivery system evaluation.\ud Results: H37Rv-GFP screening yielded a hitlist of 7 compounds at an MIC99 between 0.39\ud and 1.56 μM. MGB-362 and MGB-364 displayed intracellular mycobactericidal activity\ud against Mtb HN878 at MIC50 of 4.09 μM and 4.19 μM respectively, whilst being non-toxic.\ud Subsequent encapsulation into NIVs demonstrated a 1.6 and 2.1-fold increased intracellular\ud mycobacterial activity, similar to that of rifampicin when compared to MGB alone formulation\ud Conclusions: MGBs anti-mycobacterial activities together with non-toxic properties indicate\ud that MGB compounds constitute an important new class of drug/chemical entity, which holds\ud promise in future anti-TB therapy. Furthermore, NIVs ability to better deliver entrapped MGB\ud compounds to an intracellular Mtb infection has provided merit for further preclinical\ud evaluation.

Dimethyl sulfoxide (DMSO) is currently employed across the biomedical field, from cryopreservation to in vitro assays, despite the fact that it has been shown to have an assortment of biologically relevant effects. The amphiphilic nature of DMSO along with its relatively low toxicity at dilute concentrations make it a challenging solvent to replace. A possible alternative is Cyrene™ (dihydrolevoglucosenone), an aprotic dipolar solvent that is derived from waste biomass. In addition to being a green solvent, Cyrene™ has comparable solvation properties and is reported to have low toxicity. Herein the abilities of the two solvents to solubilize drug compounds and to act as non-participatory vehicles in drug discovery for antibacterials are compared. It was demonstrate that the results of standardised antimicrobial susceptibility testing do not differ between drugs prepared from either Cyrene™ or DMSO stock. Moreover, in contrast to DMSO, Cyrene™ does not offer protection from ROS mediated killing of bacteria and may therefore be an improvement over DMSO as a vehicle in antimicrobial drug discovery.