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• Journal article
  Darby JF, Vidler LR, Simpson PJ, Al-Lazikani B, Matthews SJ, Sharp SY, Pearl LH, Hoelder S, Workman Pet 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
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  • Citations: 5
• Conference paper
  Nwankwo 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
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• Journal article
  Switzer A, Burchell L, McQuail J, Wigneshweraraj Set 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: 0021-9193

  Bacteria 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 article
  Kamal F, Glanville N, Xia W, Bakhsoliani E, Aniscenko J, Bartlett NW, Edwards MR, Johnston SL, Singanayagam Aet 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
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• Journal article
  McQuail J, Switzer A, Burchell L, Wigneshweraraj Set 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: 0021-9258

  The 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 article
  Thomson M, Nunta K, Cheyne A, liu Y, Garza-Garcia A, Larrouy-Maumus Get 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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• Journal article
  Rapun-Araiz B, Haag AF, De Cesare V, Gil C, Dorado-Morales P, Penades JR, Lasa Iet al., 2020,

  Systematic reconstruction of the complete two-component sensorial network in staphylococcus aureus.

  , mSystems, Vol: 5, Pages: 1-16, ISSN: 2379-5077

  In bacteria, adaptation to changes in the environment is mainly controlled through two-component signal transduction systems (TCSs). Most bacteria contain dozens of TCSs, each of them responsible for sensing a different range of signals and controlling the expression of a repertoire of target genes (regulon). Over the years, identification of the regulon controlled by each individual TCS in different bacteria has been a recurrent question. However, limitations associated with the classical approaches used have left our knowledge far from complete. In this report, using a pioneering approach in which a strain devoid of the complete nonessential TCS network was systematically complemented with the constitutively active form of each response regulator, we have reconstituted the regulon of each TCS of S. aureus in the absence of interference between members of the family. Transcriptome sequencing (RNA-Seq) and proteomics allowed us to determine the size, complexity, and insulation of each regulon and to identify the genes regulated exclusively by one or many TCSs. This gain-of-function strategy provides the first description of the complete TCS regulon in a living cell, which we expect will be useful to understand the pathobiology of this important pathogen.IMPORTANCE Bacteria are able to sense environmental conditions and respond accordingly. Their sensorial system relies on pairs of sensory and regulatory proteins, known as two-component systems (TCSs). The majority of bacteria contain dozens of TCSs, each of them responsible for sensing and responding to a different range of signals. Traditionally, the function of each TCS has been determined by analyzing the changes in gene expression caused by the absence of individual TCSs. Here, we used a bacterial strain deprived of the complete TC sensorial system to introduce, one by one, the active form of every TCS. This gain-of-function strategy allowed us to identify the changes in gene expression conferred by each TCS wit

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• Journal article
  Vincent CM, Dionne MS, 2020,

  Disparate regulation of<i>imd</i>drives sex differences in infection pathology in<i>Drosophila melanogaster</i>

  <jats:title>Abstract</jats:title><jats:p>Male and female animals exhibit differences in infection outcomes. One possible source of sexually dimorphic immunity is sex-specific costs of immune activity or pathology, but little is known about the independent effects of immune-induced versus microbe-induced pathology, and whether these may differ for the sexes. Here, through measuring metabolic and physiological outputs in wild-type and immune-compromised<jats:italic>Drosophila melanogaster</jats:italic>, we test whether the sexes are differentially impacted by these various sources of pathology and identify a critical regulator of this difference. We find that the sexes exhibit differential immune activity but similar bacteria-derived metabolic pathology. We show that female-specific immune-inducible expression of<jats:italic>PGRP-LB</jats:italic>, a negative regulator of the Imd pathway, enables females to reduce immune activity in response to reductions in bacterial numbers. In the absence of<jats:italic>PGRP-LB</jats:italic>, females are more resistant of infection, confirming the functional importance of this regulation and suggesting that female-biased immune restriction comes at a cost.</jats:p>

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• Journal article
  Fisch D, Clough B, Domart M-C, Encheva V, Bando H, Snijders AP, Collinson LM, Yamamoto M, Shenoy AR, Frickel E-Met al., 2020,

  Human GBP1 differentially targets salmonella and toxoplasma to license recognition of microbial ligands and caspase-mediated death

  , Cell Reports, Vol: 32, Pages: 1-22, ISSN: 2211-1247

  Interferon-inducible guanylate-binding proteins (GBPs) promote cell-intrinsic defense through host cell death. GBPs target pathogens and pathogen-containing vacuoles and promote membrane disruption for release of microbial molecules that activate inflammasomes. GBP1 mediates pyroptosis or atypical apoptosis of Salmonella Typhimurium (STm)- or Toxoplasma gondii (Tg)- infected human macrophages, respectively. The pathogen-proximal detection-mechanisms of GBP1 remain poorly understood, as humans lack functional immunity-related GTPases (IRGs) that assist murine Gbps. Here, we establish that GBP1 promotes the lysis of Tg-containing vacuoles and parasite plasma membranes, releasing Tg-DNA. In contrast, we show GBP1 targets cytosolic STm and recruits caspase-4 to the bacterial surface for its activation by lipopolysaccharide (LPS), but does not contribute to bacterial vacuole escape. Caspase-1 cleaves and inactivates GBP1, and a cleavage-deficient GBP1D192E mutant increases caspase-4-driven pyroptosis due to the absence of feedback inhibition. Our studies elucidate microbe-specific roles of GBP1 in infection detection and its triggering of the assembly of divergent caspase signaling platforms.

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• Journal article
  Ritchie AI, Singanayagam A, 2020,

  Metagenomic Characterization of the Respiratory Microbiome A Piece de Resistance

  , AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 202, Pages: 321-322, ISSN: 1073-449X
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  • Citations: 3

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