Latest Publications
Antimicrobial triazinedione inhibitors of the translocase MraY–protein E interaction site: synergistic effects with bacitracin imply a new mechanism of action
Julia A. Fairbairn, Rachel V. Kerr, Nika-Kare A. Pierre-White, Anthony Jacovides, Becca W. A. Baileeves, Phillip J. Stansfeld, Gerhard Bringmann, Andrew T. Merritt and Timothy D. H. Bugg
Escherichia coli translocase MraY is the target for bacteriolytic protein E from bacteriophage fX174, interacting at a site close to Phe-288 on helix 9, on the extracellular face of the protein. A peptide motif Arg-Trp-x-x-Trp from protein E was used to design a set of triazinedione peptidomimetics, which inhibit particulate MraY (6d IC50 48 µM), and show antimicrobial activity against Gram-negative and Gram-positive antibiotic-resistant clinical strains (7j MIC Acinetobacter baumannii 16 µg/mL, Staphyloccoccus aureus MRSA 2-4 µg/mL). Docking against a predicted structure for E. coli MraY revealed two possible binding sites close to helix 9, the binding site for protein E. Antimicrobial activity of analogue 6j was found to be synergistic with bacitracin in Micrococcus flavus, consistent with a link between this inhibition site and undecaprenyl phosphate uptake. Alkaloid michellamine B, also predicted to bind in the cleft adjacent to helix 9, was also found to be synergistic with bacitracin. These data provide experimental evidence that the unusual hydrophobic cleft adjacent to helix 9 in MraY is involved in uptake of undecaprenyl phosphate, in addition to recently identified transporters UptA and PopT, and that this process can be targetted by small molecules as a novel antibacterial mechanism.
A comparative study of ionic pesticide sorption and degradation in contrasting Brazilian soils and the development of a novel 3-Phase Assay to assess sorption reversibility
Baudin, Nastasia, Garrod, Mark, Bramke, Irene, Mckillican, Carol, Schafer, Hendrik, Hand, Laurence, Cione, Ana, Bending, Gary D, Marshall, Samantha
Brazilian soils have distinctive characteristics to European and North American soils which are typically used to investigate pesticide fate. This study aimed to compare soil–water partition coefficient (Kd), reversibility of adsorption and degradation half-life (DT50) of 5 pesticides covering a wide range of physico-chemical properties in contrasting Brazilian soils and a temperate (UK) alfisol soil, and to study their relationship with soil OM, clay and expandable clay content, CEC and pH. The results showed that pesticide behaviour in Brazilian soils was not systematically different from those in European and North American soils. The 3PA was shown to be a reliable and simple method for assessing pesticide desorption in soil and could be adapted to assess pesticide bioavailability. The use of the 3PA allowed a more thorough explanation of the observed differences in degradation behaviour between the compounds.
MCC950 Mitigates SIRT3-NLRP3-driven Inflammation and Rescues Post-Stroke Neurogenesis
Prakash R., Waseem A., Siddiqui A.J., Naim M., Khan M.A., Robertson A.A.B., Boltze J., Raza S.S.
after ischemic stroke. The objective of this study was to examine the potential mechanism by which the SIRT3-NLRP3 inflammasome affects neural stem and progenitor cells (NSPCs) after transient middle cerebral artery occlusion (tMCAO) in rats. Overall, our results suggest that protecting NSPCs and neurogenesis in the ischemically damaged brain by mitigating the impact of the SIRT3-NLRP3 inflammasome may be a feasible treatment strategy for ischemic stroke.
Inference of multiple mergers while dating a pathogen phylogeny
Helekal, David, Koskela, Jere and Didelot, Xavier
Here we consider the problem of detecting the presence of multiple mergers in the context of dating a phylogeny, that is determining the date of each of the nodes. We use the Lambda-coalescent theory as a modelling framework and show how Bayesian inference can be efficiently performed using a Billera-Holmes- Vogtmann space embedding and a customised Markov Chain Monte Carlo sampling scheme. We applied this new analysis methodology to a large number of simulated datasets to show that it is possible to infer if and when multiple merger events occurred, and that the phylogenetic dating is improved as a result of taking this information into account. We also analysed real datasets of Vibrio cholerae and Mycobacterium tuberculosis to demonstrate the relevance of our approach to real pathogen evolutionary epidemiology. We have implemented our new methodology in a R package which is freely available at https://github.com/dhelekal/MMCTime.
MIBiG 4.0: advancing biosynthetic gene cluster curation through global collaboration
Zdouc, Mitja M. et al inc. Alberti, F
Specialized or secondary metabolites are small molecules of biological origin, often showing potent biological activities with applications in agriculture, engineering and medicine. Usually, the biosynthesis of these natural products is governed by sets of co-regulated and physically clustered genes known as biosynthetic gene clusters (BGCs). To share information about BGCs in a standardized and machine-readable way, the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard and repository was initiated in 2015. Here, we describe MIBiG version 4.0, an extensive update to the data repository and the underlying data standard.
Single-Cell Analysis with Spatiotemporal Control of Local pH
Kelsey Cremin, Gabriel N. Meloni, Orkun S. Soyer, Patrick R. Unwin
This work presents an experimental platform combining scanning ion conductance microscopy (SICM) with confocal laser scanning microscopy (CLSM), using intra- and extracellular pH indicator dyes to study the impact of acid delivery on individual HeLa cells within a population.. We find a strong dependency between the intracellular pH and the extracellular pH gradient imposed by local acid delivery. Postdelivery intracellular pH recovery depends on the extent of the acid challenge, with cells exposed to lower pH not returning to basal intracellular pH values after the extracellular pH recovers. This is a unique method for concentration-gradient challenge studies of cell populations that will have broad applications in cell biology. SICM can be used to deliver different chemicals and enables a wide range of local conditions to be applied across a cell population, for which the effects can be investigated at the single-cell level.