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  • Becker, K., et al. (författare)
  • Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
  • 2021
  • Ingår i: EBioMedicine. - : Elsevier B.V.. - 2352-3964. ; 73
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The clinical-stage drug candidate EBL-1003 (apramycin) represents a distinct new subclass of aminoglycoside antibiotics for the treatment of drug-resistant infections. It has demonstrated best-in-class coverage of resistant isolates, and preclinical efficacy in lung infection models. However, preclinical evidence for its utility in other disease indications has yet to be provided. Here we studied the therapeutic potential of EBL-1003 in the treatment of complicated urinary tract infection and acute pyelonephritis (cUTI/AP). Methods: A combination of data-base mining, antimicrobial susceptibility testing, time-kill experiments, and four murine infection models was used in a comprehensive assessment of the microbiological coverage and efficacy of EBL-1003 against Gram-negative uropathogens. The pharmacokinetics and renal toxicology of EBL-1003 in rats was studied to assess the therapeutic window of EBL-1003 in the treatment of cUTI/AP. Findings: EBL-1003 demonstrated broad-spectrum activity and rapid multi-log CFU reduction against a phenotypic variety of bacterial uropathogens including aminoglycoside-resistant clinical isolates. The basicity of amines in the apramycin molecule suggested a higher increase in positive charge at urinary pH when compared to gentamicin or amikacin, resulting in sustained drug uptake and bactericidal activity, and consequently in potent efficacy in mouse infection models. Renal pharmacokinetics, biomarkers for toxicity, and kidney histopathology in adult rats all indicated a significantly lower nephrotoxicity of EBL-1003 than of gentamicin. Interpretation: This study provides preclinical proof-of-concept for the efficacy of EBL-1003 in cUTI/AP. Similar efficacy but lower nephrotoxicity of EBL-1003 in comparison to gentamicin may thus translate into a higher safety margin and a wider therapeutic window in the treatment of cUTI/API. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section. © 2021 The Author(s)
  • Becker, K., et al. (författare)
  • Efficacy of EBL-1003 (apramycin) against Acinetobacter baumannii lung infections in mice
  • 2021
  • Ingår i: Clinical Microbiology and Infection. - : Elsevier B.V.. - 1198-743X .- 1469-0691. ; 27:9, s. 1315-
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: Novel therapeutics are urgently required for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) causing critical infections with high mortality. Here we assessed the therapeutic potential of the clinical-stage drug candidate EBL-1003 (crystalline free base of apramycin) in the treatment of CRAB lung infections. Methods: The genotypic and phenotypic susceptibility of CRAB clinical isolates to aminoglycosides and colistin was assessed by database mining and broth microdilution. The therapeutic potential was assessed by target attainment simulations on the basis of time–kill kinetics, a murine lung infection model, comparative pharmacokinetic analysis in plasma, epithelial lining fluid (ELF) and lung tissue, and pharmacokinetic/pharmacodynamic (PKPD) modelling. Results: Resistance gene annotations of 5451 CRAB genomes deposited in the National Database of Antibiotic Resistant Organisms (NDARO) suggested >99.9% of genotypic susceptibility to apramycin. Low susceptibility to standard-of-care aminoglycosides and high susceptibility to EBL-1003 were confirmed by antimicrobial susceptibility testing of 100 A. baumannii isolates. Time–kill experiments and a mouse lung infection model with the extremely drug-resistant CRAB strain AR Bank #0282 resulted in rapid 4-log CFU reduction both in vitro and in vivo. A single dose of 125 mg/kg EBL-1003 in CRAB-infected mice resulted in an AUC of 339 h × μg/mL in plasma and 299 h × μg/mL in ELF, suggesting a lung penetration of 88%. PKPD simulations suggested a previously predicted dose of 30 mg/kg in patients (creatinine clearance (CLCr) = 80 mL/min) to result in >99% probability of –2 log target attainment for MICs up to 16 μg/mL. Conclusions: This study provides proof of concept for the efficacy of EBL-1003 in the treatment of CRAB lung infections. Broad in vitro coverage, rapid killing, potent in vivo efficacy, and a high probability of target attainment render EBL-1003 a strong therapeutic candidate for a priority pathogen for which treatment options are very limited. © 2020 The Author(s)
  • Nilsson, C. L., et al. (författare)
  • Use of ENCODE Resources to Characterize Novel Proteoforms and Missing Proteins in the Human Proteome
  • 2015
  • Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 14:2, s. 603-608
  • Tidskriftsartikel (refereegranskat)abstract
    • We describe the utility of integrated strategies that employ both translation of ENCODE data and major proteomic technology pillars to improve the identification of the "missing proteins", novel proteoforms, and PTMs. On one hand, databases in combination with bioinformatic tools are efficiently utilized to establish microarray-based transcript analysis and supply rapid protein identifications in clinical samples. On the other hand, sequence libraries are the foundation of targeted protein identification and quantification using mass spectrometric and immunoaffinity techniques. The results from combining proteoENCODEdb searches with experimental mass spectral data indicate that some alternative splicing forms detected at the transcript level are in fact translated to proteins. Our results provide a step toward the directives of the C-HPP initiative and related biomedical research.
  • Dahlin, Andreas P., et al. (författare)
  • Poly(dimethylsiloxane)-Based Microchip for Two-Dimensional Solid-Phase Extraction-Capillary Electrophoresis with an Integrated Electrospray Emitter Tip
  • 2005
  • Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 77:16, s. 5356-5363
  • Tidskriftsartikel (refereegranskat)abstract
    • A microchip in poly(dimethylsiloxane) (PDMS) for in-line solid-phase extraction-capillary electrophoresis-electrospray ionization-time-of-flight mass spectrometry (SPE-CE-ESI-TOF-MS) has been developed and evaluated. The chip was fabricated in a novel one-step procedure where mixed PDMS was cast over steel wires in a mold. The removed wires defined 50-um cylindrical channels. Fused-silica capillaries were inserted into the structure in a tight fit connection. The inner walls of the inserted fused-silica capillaries and the PDMS microchip channels were modified with a positively charged polymer, PolyE-323. The chip was fabricated in a two-level cross design. The channel at the lower level was packed with 5-um hyper-cross-linked polystyrene beads acting as a SPE medium used for desalting. The upper level channel acted as a CE channel and ended in an integrated emitter tip coated with conducting graphite powder to facilitate the electrical contact for sheathless ESI. An overpressure continuously provided fresh CE electrolyte independently of the flows in the different levels. Further studies were carried out in order to investigate the electrophoretic and flow rate properties of the chip. Finally, six-peptide mixtures, in different concentrations, dissolved in physiological salt solution was injected, desalted, separated, and sprayed into the mass spectrometer for analysis with a limit of detection in femtomole levels.
  • Fridjonsdottir, Elva, et al. (författare)
  • Mass spectrometry imaging identifies abnormally elevated brain L-DOPA levels and extrastriatal monoaminergic dysregulation in L-DOPA-induced dyskinesia
  • 2021
  • Ingår i: Science Advances. - : AMER ASSOC ADVANCEMENT SCIENCE. - 2375-2548. ; 7:2
  • Tidskriftsartikel (refereegranskat)abstract
    • L-DOPA treatment for Parkinson's disease frequently leads to dyskinesias, the pathophysiology of which is poorly understood. We used MALDI-MSI to map the distribution of L-DOPA and monoaminergic pathways in brains of dyskinetic and nondyskinetic primates. We report elevated levels of L-DOPA, and its metabolite 3-O-methyldopa, in all measured brain regions of dyskinetic animals and increases in dopamine and metabolites in all regions analyzed except the striatum. In dyskinesia, dopamine levels correlated well with L-DOPA levels in extrastriatal regions, such as hippocampus, amygdala, bed nucleus of the stria terminalis, and cortical areas, but not in the striatum. Our results demonstrate that L-DOPA-induced dyskinesia is linked to a dysregulation of L-DOPA metabolism throughout the brain. The inability of extrastriatal brain areas to regulate the formation of dopamine during L-DOPA treatment introduces the potential of dopamine or even L-DOPA itself to modulate neuronal signaling widely across the brain, resulting in unwanted side effects.
  • Fridjonsdottir, Elva, et al. (författare)
  • Mass spectrometry imaging reveals brain-region specific changes in metabolism and acetylcholine levels in experimental Parkinson’s disease and L-DOPA-induced dyskinesia
  • Annan publikation (övrigt vetenskapligt)abstract
    • There is evidence that cholinergic alterations are linked to various motor and non-motor symptoms of Parkinson’s disease. We therefore used mass spectrometry imaging to investigate regional changes in acetylcholine abundance in the brain of a non-human primate model of Parkinson’s disease (PD) and L-DOPA-induced dyskinesia (LID). We also present an experimental design for performing untargeted analysis using MALDI-MSI with multiple experiments incorporating quality control samples to monitor experimental variability. We observed that MPTP treatment (i) led to reductions in putaminal acetylcholine levels that persisted after L-DOPA treatment and (ii) appeared to induce a shift of choline metabolism from α-glycerophosphocholine towards betaine. LID animals exhibited reduced levels of various metabolites important for brain homeostasis including S-adenosylmethionine, glutathione, adenosine monophosphate, and acylcarnitines. The vasculature marker heme B was upregulated in the putamen of LID animals, suggesting increased blood-flow in the dyskinetic putamen. These results provide new insights into pathological choline-related metabolic changes in PD and LID.  
  • Fridjonsdottir, Elva, et al. (författare)
  • Region-Specific and Age-Dependent Multitarget Effects of Acetylcholinesterase Inhibitor Tacrine on Comprehensive Neurotransmitter Systems
  • 2022
  • Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 17:1, s. 147-158
  • Tidskriftsartikel (refereegranskat)abstract
    • Regional brain distribution and metabolism of neurotransmitters and their response to drug treatment are fundamentally important for understanding the central effects of neuroactive substances. We used matrix-assisted laser desorption/ionization mass spectrometry imaging in combination with multivariate analysis to visualize in anatomical detail metabolic effects of aging and tacrine-mediated acetylcholinesterase inhibition on comprehensive neurotransmitter systems in multiple mouse brain regions of 12-week-old and 14-month-old mice. We detected age-related increases in 3,4-dihydroxyphenylacetaldehyde and histamine, indicating oxidative stress and aging deficits in astrocytes. Tacrine had a significant impact on the metabolism of neurotransmitters in both age groups; predominantly, there was an increased norepinephrine turnover throughout the brain and decreased 3-methoxy tyramine, a marker for dopamine release, in the striatum. The striatal levels of histamine were only elevated after tacrine administration in the older animals. Our results demonstrated that tacrine is a multitarget and region-specific neuroactive agent, inducing age-specific responses. Although well-studied, the complete mechanisms of the action of tacrine are not fully understood, and the current findings reveal features that may help explain its treatment-related effectiveness and central side effects.
  • Hulme, Heather E., et al. (författare)
  • Mass spectrometry imaging identifies palmitoylcarnitine as an immunological mediator during Salmonella Typhimurium infection
  • 2017
  • Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Salmonella Typhimurium causes a self-limiting gastroenteritis that may lead to systemic disease. Bacteria invade the small intestine, crossing the intestinal epithelium from where they are transported to the mesenteric lymph nodes (MLNs) within migrating immune cells. MLNs are an important site at which the innate and adaptive immune responses converge but their architecture and function is severely disrupted during S. Typhimurium infection. To further understand host-pathogen interactions at this site, we used mass spectrometry imaging (MSI) to analyse MLN tissue from a murine model of S. Typhimurium infection. A molecule, identified as palmitoylcarnitine (PalC), was of particular interest due to its high abundance at loci of S. Typhimurium infection and MLN disruption. High levels of PalC localised to sites within the MLNs where B and T cells were absent and where the perimeter of CD169(+) sub capsular sinus macrophages was disrupted. MLN cells cultured ex vivo and treated with PalC had reduced CD4(+) CD25(+) T cells and an increased number of B220(+) CD19(+) B cells. The reduction in CD4(+) CD25(+) T cells was likely due to apoptosis driven by increased caspase-3/7 activity. These data indicate that PalC significantly alters the host response in the MLNs, acting as a decisive factor in infection outcome.
  • Hulme, Heather, et al. (författare)
  • Simultaneous mass spectrometry imaging of multiple neuropeptides in the brain and alterations induced by experimental parkinsonism and L-DOPA therapy
  • 2020
  • Ingår i: Neurobiology of Disease. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 0969-9961 .- 1095-953X. ; 137
  • Tidskriftsartikel (refereegranskat)abstract
    • Neuropeptides are important signalling molecules in the brain and alterations in their expression levels have been linked to neurological disorders such as Parkinson's disease. It is challenging to map neuropeptide changes across and within brain regions because of their low in vivo concentrations and complex post-translational processing. Consequently, the role of neuropeptides in Parkinson's disease is not well understood. Thus, we have developed and evaluated a method to image multiple neuropeptides simultaneously in both rat and primate brain tissue sections by matrix-assisted laser desorption/ionisation mass spectrometry imaging at high lateral resolution. Using a unilateral 6-hydroxydopamine rat model of Parkinson's disease, we imaged changes in enkephalins, dynorphins, tachykinins and neurotensin associated with the dopaminergic denervation and L-DOPA treatment in multiple brain regions. L-DOPA administration significantly affected neuropeptides in the globus pallidus, while neuropeptides in the caudate-putamen were mostly affected by dopamine depletion. Using high lateral resolution imaging, we observed an increase of neurotensin in the dorsal sub-region of the globus pallidus after dopamine depletion. This study highlights the capacity of mass spectrometry imaging to elucidate the dynamics of neuropeptide signalling during Parkinson's disease and its treatment.
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