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Journal articleYebra G, Haag AF, Neamah MM, et al., 2020,
Massive genome decay and insertion sequence expansion drive the evolution of a novel host-restricted bacterial pathogen
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>The emergence of new pathogens is a major threat to public and veterinary health. Changes in bacterial habitat such as those associated with a switch in host or disease tropism are often accompanied by genetic adaptation. <jats:italic>Staphylococcus aureus</jats:italic> is a multi-host bacterial species comprising strains with distinct tropisms for human and livestock species. A microaerophilic subspecies, <jats:italic>Staphylococcus aureus</jats:italic> subsp. <jats:italic>anaerobius</jats:italic>, is responsible for outbreaks of Morel’s disease, a lymphadenitis in small ruminants. However, the evolutionary history of <jats:italic>S. aureus</jats:italic> subsp. <jats:italic>anaerobius</jats:italic> and its relatedness to <jats:italic>S. aureus</jats:italic> are unknown.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Evolutionary genomic analyses of clinical <jats:italic>S. aureus</jats:italic> subsp. <jats:italic>anaerobius</jats:italic> isolates revealed a highly conserved clone that descended from a <jats:italic>S. aureus</jats:italic> progenitor about 1000 years ago before differentiating into distinct lineages representing African and European isolates. <jats:italic>S. aureus</jats:italic> subsp. <jats:italic>anaerobius</jats:italic> has undergone limited clonal expansion, with a restricted population size, and an evolutionary rate 10-fold slower than <jats:italic>S. aureus</jats:italic>. The transition to its current restricted ecological niche involved acquisition of a pathogenicity island encoding a ruminant host-specific effector of abscess formation, several large chromosomal re-arrangements, and the accumulation of at least 205 pse
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Journal articleTaylor H, Serrano-Contreras JI, McDonald JAK, et al., 2020,
Multiomic features associated with mucosal healing and inflammation in paediatric Crohn's disease
, Alimentary Pharmacology and Therapeutics, Vol: 52, Pages: 1491-1502, ISSN: 0269-2813BACKGROUND: The gastrointestinal microbiota has an important role in mucosal immune homoeostasis and may contribute to maintaining mucosal healing in Crohn's disease (CD). AIM: To identify changes in the microbiota, metabolome and protease activity associated with mucosal healing in established paediatric CD. METHODS: Twenty-five participants aged 3-18 years with CD, disease duration of over 6 months, and maintenance treatment with biological therapy were recruited. They were divided into a low calprotectin group (faecal calprotectin <100 μg/g, "mucosal healing," n = 11), and a high calprotectin group (faecal calprotectin >100 μg/g, "mucosal inflammation," n = 11). 16S gene-based metataxonomics, 1 H-NMR spectroscopy-based metabolic profiling and protease activity assays were performed on stool samples. RESULTS: Relative abundance of Dialister species was six times greater in the low calprotectin group (q = 0.00999). Alpha and beta diversity, total protease activity and inferred metagenomic profiles did not differ between groups. Pentanoate (valerate) and lysine were principal discriminators in a machine-learning model which differentiated high and low calprotectin samples using NMR spectra (R2 0.87, Q2 0.41). Mean relative concentration of pentanoate was 1.35-times greater in the low calprotectin group (95% CI 1.03-1.68, P = 0.036) and was positively correlated with Dialister. Mean relative concentration of lysine was 1.54-times greater in the high calprotectin group (95% CI 1.05-2.03, P = 0.028). CONCLUSIONS: This multiomic study identified an increase in Dialister species and pentanoate, and a decrease in lysine, in patients with "mucosal healing." It supports further investigation of these as potential novel therapeutic targets in CD.
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Journal articleFarne H, Kumar K, Ritchie AI, et al., 2020,
Repurposing existing drugs for the treatment of COVID-19
, Annals of the American Thoracic Society, Vol: 17, Pages: 1186-1194, ISSN: 1546-3222The rapid global spread and significant mortality associated with the coronavirus disease (COVID-19) caused by SARS-CoV-2 viral infection has spurred an urgent race to find effective treatments. Repurposing existing drugs is a particularly attractive approach as pharmacokinetic and safety data already exist, thus development can leapfrog straight to clinical trials of efficacy, generating results far more quickly than de novo drug development. This review summarizes the state of play for the principle drugs identified as candidates to be repurposed for treating COVID-19 grouped by broad mechanism of action: antiviral, immune enhancing, and anti-inflammatory or immunomodulatory. Patient selection, particularly with regard to disease stage, is likely to be key. To date only dexamethasone and remedesivir have been shown to be effective, but several other promising candidates are in trials.
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Journal articleArmstrong-James D, Youngs J, Bicanic T, et al., 2020,
Confronting and mitigating the risk of COVID-19 Associated Pulmonary Aspergillosis (CAPA)
, European Respiratory Journal, Vol: 56, Pages: 1-10, ISSN: 0903-1936Cases of COVID-19 associated pulmonary aspergillosis (CAPA) are being increasingly reported and physicians treating patients with COVID-19-related lung disease need to actively consider these fungal co-infections.The SARS-CoV-2 (COVID-19) virus causes a wide spectrum of disease in healthy individuals as well as those with common comorbidities [1]. Severe COVID-19 is characterised acute respiratory distress syndrome (ARDS) secondary to viral pneumonitis, treatment of which may require mechanical ventilation or extracorporeal membrane oxygenation (ECMO) [2]. Clinicians are alert to the possibility of bacterial co-infection as a complication of lower respiratory tract viral infection; for example a recent review found that 72% of patients with COVID-19 received antimicrobial therapy [3]. However, the risk of fungal co-infection, in particular COVID-19 associated pulmonary aspergillosis (CAPA), remains underappreciated.Fungal disease consistent with invasive aspergillosis (IA) has been observed with other severe Coronaviruses such as Severe Acute Respiratory Syndrome (SARS-CoV-2003) [4, 5] and Middle East Respiratory Syndrome (MERS-CoV) [6]. From the outset of the COVID-19 pandemic, there were warning signs of secondary invasive fungal infection; Aspergillus flavus was isolated from the respiratory tract from one of 99 patients in the first COVID-19 cohort from Wuhan to be reported in any detail [2] and Aspergillus spp. were isolated from 2/52 (3.8%) of a subsequent cohort of critically unwell patients from this region [7]. More recently, retrospective case series from Belgium [8], France [9], The Netherlands [10] and Germany [11] have reported evidence of CAPA in an alarming 20–35% of mechanically ventilated patients.
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Journal articleDarby JF, Vidler LR, Simpson PJ, et al., 2020,
Solution structure of the Hop TPR2A domain and investigation of target druggability by NMR, biochemical and in silico approaches
, SCIENTIFIC REPORTS, Vol: 10, ISSN: 2045-2322- Author Web Link
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Conference paperNwankwo L, Armstrong-James D, Shah A, 2020,
Use of Isavuconazole MIC to guide dosing in the management of Aspergillosis in patients with pulmonary disease
, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936 -
Journal articleSwitzer A, Burchell L, McQuail J, et al., 2020,
The adaptive response to long-term nitrogen starvation in Escherichia coli requires the breakdown of allantoin.
, Journal of Bacteriology, Vol: 202, Pages: 1-11, ISSN: 0021-9193Bacteria initially respond to nutrient starvation by eliciting large-scale transcriptional changes. The accompanying changes in gene expression and metabolism allow the bacterial cells to effectively adapt to the nutrient starved state. How the transcriptome subsequently changes as nutrient starvation ensues is not well understood. We used nitrogen (N) starvation as a model nutrient starvation condition to study the transcriptional changes in Escherichia coli experiencing long-term N starvation. The results reveal that the transcriptome of N starved E. coli undergoes changes that are required to maximise chances of viability and to effectively recover growth when N starvation conditions become alleviated. We further reveal that, over time, N starved E. coli cells rely on the degradation of allantoin for optimal growth recovery when N becomes replenished. This study provides insights into the temporally coordinated adaptive responses that occur in E. coli experiencing sustained N starvation.IMPORTANCE Bacteria in their natural environments seldom encounter conditions that support continuous growth. Hence, many bacteria spend the majority of their time in states of little or no growth due to starvation of essential nutrients. To cope with prolonged periods of nutrient starvation, bacteria have evolved several strategies, primarily manifesting themselves through changes in how the information in their genes is accessed. How these coping strategies change over time under nutrient starvation is not well understood and this knowledge is not only important to broaden our understanding of bacterial cell function, but also to potentially find ways to manage harmful bacteria. This study provides insights into how nitrogen starved Escherichia coli bacteria rely on different genes during long term nitrogen starvation.
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Journal articleKamal F, Glanville N, Xia W, et al., 2020,
Beclomethasone has lesser suppressive effects on inflammation and anti-bacterial immunity than Fluticasone or Budesonide in experimental infection models.
, Chest, Vol: 158, Pages: 947-951, ISSN: 0012-3692 -
Journal articleMcQuail J, Switzer A, Burchell L, et al., 2020,
The RNA-binding protein Hfq assembles into foci-like structures in nitrogen starved Escherichia coli
, Journal of Biological Chemistry, Vol: 295, Pages: 12355-12367, ISSN: 0021-9258The initial adaptive responses to nutrient depletion in bacteria often occur at the level of gene expression. Hfq is an RNA-binding protein present in diverse bacterial lineages and contributes to many different aspects of RNA metabolism during gene expression. Using photoactivated localization microscopy (PALM) and single molecule tracking, we demonstrate that Hfq forms a distinct and reversible focus-like structure in Escherichia coli specifically experiencing long-term nitrogen (N) starvation. Using the ability of T7 phage to replicate in N-starved bacteria as a biological probe of E. coli cell function during N starvation, we demonstrate that Hfq foci have a role in the adaptive response of E. coli to long-term N starvation. We further show that Hfq foci formation does not depend on gene expression once N starvation has set in and occurs independently of the transcription factor N-regulatory protein C (NtrC), that activates the initial adaptive response to N starvation in E. coli These results serve as a paradigm to demonstrate that bacterial adaptation to long-term nutrient starvation can be spatiotemporally coordinated and can occur independently of de novo gene expression during starvation.
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Journal articleThomson M, Nunta K, Cheyne A, et al., 2020,
Modulation of the cAMP levels with a conserved actinobacteria phosphodiesterase enzyme reduces antimicrobial tolerance in mycobacteria
<jats:title>Abstract</jats:title><jats:p>Antimicrobial tolerance (AMT) is the gateway to the development of antimicrobial resistance (AMR) and is therefore a major issue that needs to be addressed.</jats:p><jats:p>The second messenger cyclic-AMP (cAMP), which is conserved across all taxa, is involved in propagating signals from environmental stimuli and converting these into a response. In bacteria, such as<jats:italic>M. tuberculosis</jats:italic>,<jats:italic>P. aeruginosa</jats:italic>,<jats:italic>V. cholerae</jats:italic>and<jats:italic>B. pertussis</jats:italic>, cAMP has been implicated in virulence, metabolic regulation and gene expression. However, cAMP signalling in mycobacteria is particularly complex due to the redundancy of adenylate cyclases, which are enzymes that catalyse the formation of cAMP from ATP, and the poor activity of the only known phosphodiesterase (PDE) enzyme, which degrades cAMP into 5’- AMP.</jats:p><jats:p>Based on these two features, the modulation of this system with the aim of investigating cAMP signalling and its involvement in AMT in mycobacteria id difficult.</jats:p><jats:p>To address this pressing need, we identified a new cAMP-degrading phosphodiesterase enzyme (Rv1339) and used it to significantly decrease the intrabacterial levels of cAMP in mycobacteria. This analysis revealed that this enzyme increased the antimicrobial susceptibility of<jats:italic>M. smegmatis</jats:italic>mc<jats:sup>2</jats:sup>155. Using a combination of metabolomics, RNA-sequencing, antimicrobial susceptibility assays and bioenergetics analysis, we were able to characterize the molecular mechanism underlying this increased susceptibility.</jats:p><jats:p>This work represents an important milestone showing that the targeting of cAMP signalling is a promising new avenue for antimicrobial development and expan
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