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• Journal article
  Slater S, Frankel G, 2020,

  Advances and challenges in studying type III secretion effectors of attaching and effacing pathogens

  , Frontiers in Cellular and Infection Microbiology, Vol: 10, Pages: 1-7, ISSN: 2235-2988
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• Journal article
  Sanchez-Garrido J, Shenoy A, 2020,

  Regulation and repurposing of nutrient sensing and autophagy in innate immunity

  , Autophagy, Vol: 17, Pages: 1571-1591, ISSN: 1554-8627

  Nutrients not only act as building blocks but also as signaling molecules. Nutrient-availability promotes cell growth and proliferation and suppresses catabolic processes, such as macroautophagy/autophagy. These effects are mediated by checkpoint kinases such as MTOR (mechanistic target of rapamycin kinase), which is activated by amino acids and growth factors, and AMP-activated protein kinase (AMPK), which is activated by low levels of glucose or ATP. These kinases have wide-ranging activities that can be co-opted by immune cells upon exposure to danger signals, cytokines or pathogens. Here, we discuss recent insight into the regulation and repurposing of nutrient-sensing responses by the innate immune system during infection. Moreover, we examine how natural mutations and pathogen-mediated interventions can alter the balance between anabolic and autophagic pathways leading to a breakdown in tissue homeostasis and/or host defense.

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• Journal article
  Broncel M, Dominicus C, Vigetti L, Nofal SD, Bartlett EJ, Touquet B, Hunt A, Wallbank BA, Federico S, Matthews S, Young JC, Tate EW, Tardieux I, Treeck Met al., 2020,

  Profiling of myristoylation in <i>Toxoplasma</i> <i>gondii</i> reveals an <i>N</i>-myristoylated protein important for host cell penetration

  , ELIFE, Vol: 9, ISSN: 2050-084X
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  • Citations: 12
• Journal article
  Walter A, Unsleber S, Rismondo J, Jorge AM, Peschel A, Grundling A, Mayer Cet al., 2020,

  Phosphoglycerol-type wall and lipoteichoic acids are enantiomeric polymers differentiated by the stereospecific glycerophosphodiesterase GlpQ (vol 295, pg 4024, 2020)

  , JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 295, Pages: 8873-8873, ISSN: 0021-9258
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• Journal article
  Schrader SM, Vaubourgeix J, Nathan C, 2020,

  Biology of antimicrobial resistance and approaches to combat it

  , SCIENCE TRANSLATIONAL MEDICINE, Vol: 12, ISSN: 1946-6234
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  • Citations: 73
• Journal article
  Sarah Wettstadt S, Lai E-M, Filloux AAM, 2020,

  Solving the puzzle: connecting a heterologous Agrobacterium tumefaciens T6SS effector to a Pseudomonas aeruginosa spike complex

  , Frontiers in Cellular and Infection Microbiology, Vol: 10, ISSN: 2235-2988

  The type VI secretion system (T6SS) is a contractile injection apparatus that translocates a spike loaded with various effectors directly into eukaryotic and prokaryotic target cells. Such T6SS spike consists of a needle-shaped trimer of VgrG proteins topped by a conical and sharp PAAR protein that facilitates puncturing of the target membrane. T6SS-delivered effector proteins can be either fused to one of the two spike proteins or interact with either in a highly specific manner. In Agrobacterium tumefaciens the T6SS effector Tde1 is targeted to its cognate VgrG1 protein. Here, we attempted to use a VgrG shuttle to deliver a heterologous T6SS effector by directing Tde1 onto a T6SS spike in Pseudomonas aeruginosa. For this, we designed chimeras between VgrG1 from A. tumefaciens and VgrG1a from P. aeruginosa and showed that modification of the spike protein hampered T6SS functionality in the presence of the Tde1 effector complex. We provide evidence suggesting that Tde1 specifically binds to the VgrG spike in the heterologous environment and propose that there are additional requirements to allow proper effector delivery and translocation. Our work sheds light on complex aspects of the molecular mechanisms of T6SS delivery and highlights some limitations on how effectors can be translocated using this nanomachine.

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• Journal article
  Stelzl LS, Mavridou DA, Saridakis E, Gonzalez D, Baldwin AJ, Ferguson SJ, Sansom MS, Redfield Cet al., 2020,

  Local frustration determines loop opening during the catalytic cycle of an oxidoreductase.

  , eLife, Vol: 9, Pages: 1-27, ISSN: 2050-084X

  Local structural frustration, the existence of mutually exclusive competing interactions, may explain why some proteins are dynamic while others are rigid. Frustration is thought to underpin biomolecular recognition and the flexibility of protein-binding sites. Here, we show how a small chemical modification, the oxidation of two cysteine thiols to a disulfide bond, during the catalytic cycle of the N-terminal domain of the key bacterial oxidoreductase DsbD (nDsbD), introduces frustration ultimately influencing protein function. In oxidized nDsbD, local frustration disrupts the packing of the protective cap-loop region against the active site allowing loop opening. By contrast, in reduced nDsbD the cap loop is rigid, always protecting the active-site thiols from the oxidizing environment of the periplasm. Our results point toward an intricate coupling between the dynamics of the active-site cysteines and of the cap loop which modulates the association reactions of nDsbD with its partners resulting in optimized protein function.

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• Journal article
  Letertre MPM, Munjoma NC, Wolfer K, Pechlivanis A, McDonald J, Hardwick RN, Cherrington NJ, Coen M, Nicholson J, Hoyles L, Swann J, Wilson Iet al., 2020,

  A two-way interaction between methotrexate and the gut microbiota of male Sprague Dawley rats

  , Journal of Proteome Research, Vol: 19, Pages: 3326-3339, ISSN: 1535-3893

  Methotrexate (MTX) is a chemotherapeutic agent that cancause a range of toxic side effects including gastrointestinal damage,hepatotoxicity, myelosuppression, and nephrotoxicity and has potentiallycomplex interactions with the gut microbiome. Following untargeted UPLCqtof-MS analysis of urine and fecal samples from male Sprague−Dawley ratsadministered at either 0, 10, 40, or 100 mg/kg of MTX, dose-dependentchanges in the endogenous metabolite profiles were detected. Semiquantitativetargeted UPLC-MS detected MTX excreted in urine as well as MTX and twometabolites, 2,4-diamino-N-10-methylpteroic acid (DAMPA) and 7-hydroxyMTX, in the feces. DAMPA is produced by the bacterial enzymecarboxypeptidase glutamate 2 (CPDG2) in the gut. Microbiota profiling(16S rRNA gene amplicon sequencing) of fecal samples showed an increase inthe relative abundance of Firmicutes over the Bacteroidetes at low doses ofMTX but the reverse at high doses. Firmicutes relative abundance was positively correlated with DAMPA excretion in feces at 48 h,which were both lower at 100 mg/kg compared to that seen at 40 mg/kg. Overall, chronic exposure to MTX appears to inducecommunity and functionality changes in the intestinal microbiota, inducing downstream perturbations in CPDG2 activity, and thusmay delay MTX detoxication to DAMPA. This reduction in metabolic clearance might be associated with increased gastrointestinaltoxicity.

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• Journal article
  Asai M, Li Y, Spiropoulos J, Cooley W, Everest D, Robertson BD, Langford PR, Newton SMet al., 2020,

  A novel biosafety level 2 compliant tuberculosis infection model using a ΔleuDΔpanCD double auxotroph of Mycobacterium tuberculosis H37Rv and Galleria mellonella

  , Virulence, Vol: 11, Pages: 811-824, ISSN: 2150-5594

  Mammalian infection models have contributed significantly to our understanding of the host-mycobacterial interaction, revealing potential mechanisms and targets for novel antimycobacterial therapeutics. However, the use of conventional mammalian models such as mice, are typically expensive, high maintenance, require specialised animal housing, and are ethically regulated. Furthermore, research using Mycobacterium tuberculosis (MTB), is inherently difficult as work needs to be carried out at biosafety level 3 (BSL3). The insect larvae of Galleria mellonella (greater wax moth), have become increasingly popular as an infection model, and we previously demonstrated its potential as a mycobacterial infection model using Mycobacterium bovis BCG. Here we present a novel BSL2 complaint MTB infection model using G. mellonella in combination with a bioluminescent ΔleuDΔpanCD double auxotrophic mutant of MTB H37Rv (SAMTB lux) which offers safety and practical advantages over working with wild type MTB. Our results show a SAMTB lux dose dependent survival of G. mellonella larvae and demonstrate proliferation and persistence of SAMTB lux bioluminescence over a 1 week infection time course. Histopathological analysis of G. mellonella, highlight the formation of early granuloma-like structures which matured over time. We additionally demonstrate the drug efficacy of first (isoniazid, rifampicin, and ethambutol) and second line (moxifloxacin) antimycobacterial drugs. Our findings demonstrate the broad potential of this insect model to study MTB infection under BSL2 conditions. We anticipate that the successful adaptation and implementation of this model will remove the inherent limitations of MTB research at BSL3 and increase tuberculosis research output.

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• Journal article
  Kiga K, Tan X-E, Ibarra-Chávez R, Watanabe S, Aiba Y, Sato'o Y, Li F-Y, Sasahara T, Cui B, Kawauchi M, Boonsiri T, Thitiananpakorn K, Taki Y, Azam AH, Suzuki M, Penadés JR, Cui Let al., 2020,

  Development of CRISPR-Cas13a-based antimicrobials capable of sequence-specific killing of target bacteria

  , Nature Communications, Vol: 11, ISSN: 2041-1723

  The emergence of antimicrobial-resistant bacteria is an increasingly serious threat to global health, necessitating the development of innovative antimicrobials. Here we report the development of a series of CRISPR-Cas13a-based antibacterial nucleocapsids, termed CapsidCas13a(s), capable of sequence-specific killing of carbapenem-resistant Escherichia coli and methicillin-resistant Staphylococcus aureus by recognizing corresponding antimicrobial resistance genes. CapsidCas13a constructs are generated by packaging programmed CRISPR-Cas13a into a bacteriophage capsid to target antimicrobial resistance genes. Contrary to Cas9-based antimicrobials that lack bacterial killing capacity when the target genes are located on a plasmid, the CapsidCas13a(s) exhibit strong bacterial killing activities upon recognizing target genes regardless of their location. Moreover, we also demonstrate that the CapsidCas13a(s) can be applied to detect bacterial genes through gene-specific depletion of bacteria without employing nucleic acid manipulation and optical visualization devices. Our data underscore the potential of CapsidCas13a(s) as both therapeutic agents against antimicrobial-resistant bacteria and nonchemical agents for detection of bacterial genes.

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