Chris Dowson publications
Profiling interactions of vaborbactam with metallo-β-lactamases
Gareth W.Langley, Ricky Cain, Jonathan, M.Tyrrell, Philip Hinchliffe, Karina Calvopiña, Catherine L.Tooke, Emma Widlake, Christopher G.Dowson, James Spencer, Timothy R.Walsh, Christopher J.Schofield, Jürgen Brem
β-Lactams are the most successful antibacterials, yet their use is threatened by resistance, importantly as caused by β-lactamases. β-Lactamases fall into two mechanistic groups, and achieving simultaneous inhibition of both β-lactamase classes remains a challenge in the field. Vaborbactam is a boronate-based inhibitor that reacts with serine-β-lactamases to form covalent complexes that mimic tetrahedral intermediates in catalysis. Our findings indicate that cyclic boronate scaffolds have the potential to inhibit the full range of β-lactamases and justify further work on the development of boronates as broad-spectrum β-lactamase inhibitors.
Chagas Disease in the Bolivian Chaco – persistent transmission indicated by childhood seroscreening study
T Hopkins, R Gonçalves, J Mamani, O Courtenay, C Bern
Chronic infection with Trypanosoma cruzi ( T. cruzi) leads to clinically significant cardiovascular and gastrointestinal disease, and treatment remains challenging. We screened for Trypanosoma cruzi infection amongst children in a rural community in the Bolivian Chaco, an area known for high prevalence. We also estimated the force of infection. This study demonstrates persistent transmission and continued high levels of T. cruzi infection, and highlights the practicality of school-based screening.
Johannes Boltze publications
Current and emerging avenues for Alzheimer's disease drug targets
Loera‐Valencia R, Duarte A, Giusti P, Zusso M, Robert P, Frisoni GB, Cattaneo A, Zille M, Boltze J, Cartier N, Buee I, Johansson G, Winblad B
Here, we review broadly recent information for potential targets that can modify Alzheimer’s disease (AD) through diverse pharmacological and non‐pharmacological approaches including gene therapy. We propose that AD could be tackled using combination therapies including Aβ and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood‐brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near‐future strategy.
Communal metabolism by Methylococcaceae and Methylophilaceae is driving rapid aerobic methane oxidation in sediments of a shallow seep near Elba, Italy
Martin Taubert, Carolina Grob, Andrew Crombie, Alexandra M Howat, Oliver J Burns, Miriam Weber, Christian Lott, Anne-Kristin Kaster, John Vollmers, Nico Jehmlich, Martin von Bergen, Yin Chen and John Colin Murrell
The release of abiotic methane from marine seeps into the atmosphere is a major source of this potent greenhouse gas. Methanotrophic microorganisms in methane seeps use methane as carbon and energy source, thus significantly mitigating global methane emissions. Here, we investigated microbial methane oxidation at the sediment–water interface of a shallow marine methane seep. The results imply that more than 50% of methane at the seep is removed by microbial oxidation at the sediment–water interface. It was also demonstrated that the methane‐oxidizing community supported a complex trophic network. Our results provide valuable eco‐physiological insights into this specialized microbial community performing an ecosystem function of global relevance.
The speciation and hybridization history of the genus Salmonella
Alexis Criscuolo, Sylvie Issenhuth-Jeanjean, Xavier Didelot, Kaisa Thorell, James Hale, Julian Parkhill, Nicholas R. Thomson, François-Xavier Weill, Daniel Falush and Sylvain Brisse
Bacteria and archaea make up most of natural diversity, but the mechanisms that underlie the origin and maintenance of prokaryotic species are poorly understood. In this paper we ask whether the Salmonella family tree is fully tree-like, with lineages splitting off sequentially from each other, or whether it in fact includes hybridization events. We explored this question by sampling the untapped diversity of Salmonella widely and by sequencing the complete genome of a representative sample of its lineages. We find that most of the time, species of Salmonella diverged vertically, but that there are some events involving rampant gene flow between distantly related lineages, which might be compared, for example, to the creation of a new species of apes by mixing the DNA of gibbons and gorillas. Our finding of long-distance hybridization poses a challenge for traditional bacterial taxonomy and for other approaches that assume that bacterial species trees can be summarized using binary splits.
Impact of autophagy and ageing on iron load and ferritin in Drosophila brain
Impaired iron metabolism has been linked to several neurodegenerative disorders. Autophagy, an intracellular degradative process dependent on the lysosomes, is involved in the regulation of ferritin and iron levels. Impaired autophagy has been associated with normal pathological aging, and neurodegeneration. Here, we show that ferritin is expressed in adult Drosophila brain and that iron and holoferritin accumulate with aging. We revealed an additional spectral feature in the iron-richest region of autophagy-deficient fly brains, consistent with iron–sulfur. This potentially arises from iron–sulfur clusters associated with altered mitochondrial iron homeostasis.