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Latest Publications

Chris Dowson publications

Bioorganic & Med Chem letters jul19Profiling 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.

Biooganic and Medicinal Chemistry Letters. August 2019

J.Mol Biol 75x100 jul19Novel and Improved Crystal Structures of H. influenzae, E. coli and P. aeruginosa Penicillin-Binding Protein 3 (PBP3) and N. gonorrhoeae PBP2: Toward a Better Understanding of β-Lactam Target-Mediated Resistance

Bellini D, Koekemoer L, Newman H, Dowson C

Penicillin and the wider family of β-lactams are the single most important family of antibiotics. The periplasmic/extra-cytoplasmic targets of penicillin are a family of enzymes with a highly conserved catalytic activity involved in the final stage of bacterial cell wall biosynthesis. These key targets are called penicillin-binding proteins (PBPs). Resistance is predominantly mediated by reducing the target drug concentration via β-lactamases; however, naturally transformable bacteria have also acquired target-mediated resistance by inter-species recombination. Here we focus on structural based interpretations of amino acid alterations associated with the emergence of resistance within clinical isolates and include new PBP3 structures along with new, and improved, PBP-β-lactam co-structures.

Journal of Molecular Biology. July 2019

Thu 15 Aug 2019, 08:05 | Tags: Biomedical Science

Chagas Disease in the Bolivian Chaco – persistent transmission indicated by childhood seroscreening study

IJID jul19T 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.

International Journal of Infectious Diseases. July 2019

Mon 12 Aug 2019, 08:13 | Tags: Biomedical Science

Johannes Boltze publications

J.Internal Medicine 75x100Current 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.

Journal of Internal Medicine. July 2019

Stem Cells Trans Med jul19 smallNeuronal Stem Cell-Drug Interactions: A Systematic Review and Meta-Analysis

Ikhsan M, Palumbo A, Rose D, Zille M, Boltze J

Stem cell therapy is a promising treatment option for neurodegenerative diseases that mostly affect geriatric patients who often suffer from comorbidities requiring multiple medications. However, not much is known about the interactions between stem cells and drugs. Here, we review the potential interactions between drugs used to treat the comorbidities or sequelae of neurodegenerative diseases and neuronal stem cells to reveal potential effects on drug safety and efficacy. Although available data were in most cases insufficient to perform robust meta‐analysis, a clear interaction between antidepressants and neuronal stem cells was identified. We reveal potential other interactions requiring further experimental investigation. We recommend that future research addresses such interactions and investigates the best combination of pharmacological interventions and neuronal stem cell treatments for more efficient and safer patient care.

Stem Cells Translational Medicine. July 2019

Fri 09 Aug 2019, 07:59

Communal metabolism by Methylococcaceae and Methylophilaceae is driving rapid aerobic methane oxidation in sediments of a shallow seep near Elba, Italy

Env Microb jul19Martin 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.

Environmental Microbiology. July 2019

Wed 07 Aug 2019, 08:22 | Tags: Environmental Bioscience

The speciation and hybridization history of the genus Salmonella

IJID jul19Alexis 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.

Microbial Genomics. July 2019

Mon 05 Aug 2019, 08:41

Impact of autophagy and ageing on iron load and ferritin in Drosophila brain

Front Cell&Dev BiolJacomin AC, Geraki K, Brooks J, Tjhin VT, Collingwood JF and Ioannis Nezis

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.

Frontiers in Cell & Developmental Biology. July 2019

Thu 01 Aug 2019, 08:18 | Tags: Biomedical Science

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