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  • Journal article
    Heeb S, Camara M, Filloux A, Williams Pet al., 2017,

    Professor Dieter Haas (1945-2017) OBITUARY

    , FEMS MICROBIOLOGY REVIEWS, Vol: 41, Pages: 597-598, ISSN: 0168-6445
  • Journal article
    Jakobsen TH, Warming AN, Vejborg RM, Moscoso JA, Stegger M, Lorenzen F, Rybtke M, Andersen JB, Petersen R, Andersen PS, Nielsen TE, Tolker-Nielsen T, Filloux A, Ingmer H, Givskov Met al., 2017,

    A broad range quorum sensing inhibitor working through sRNA inhibition

    , Scientific Reports, Vol: 7, ISSN: 2045-2322

    For the last decade, chemical control of bacterial virulence has received considerable attention. Ajoene, a sulfur-rich molecule from garlic has been shown to reduce expression of key quorum sensing regulated virulence factors in the opportunistic pathogen Pseudomonas aeruginosa. Here we show that the repressing effect of ajoene on quorum sensing occurs by inhibition of small regulatory RNAs (sRNA) in P. aeruginosa as well as in Staphylococcus aureus, another important human pathogen that employs quorum sensing to control virulence gene expression. Using various reporter constructs, we found that ajoene lowered expression of the sRNAs RsmY and RsmZ in P. aeruginosa and the small dual-function regulatory RNA, RNAIII in S. aureus, that controls expression of key virulence factors. We confirmed the modulation of RNAIII by RNA sequencing and found that the expression of many QS regulated genes encoding virulence factors such as hemolysins and proteases were lowered in the presence of ajoene in S. aureus. Importantly, our findings show that sRNAs across bacterial species potentially may qualify as targets of anti-virulence therapy and that ajoene could be a lead structure in search of broad-spectrum compounds transcending the Gram negative-positive borderline.

  • Journal article
    Sarkar P, Switzer A, Peters C, Pogliano J, Wigneshweraraj Set al., 2017,

    Phenotypic consequences of RNA polymerase dysregulation in Escherichiacoli

    , Nucleic Acids Research, Vol: 45, Pages: 11131-11143, ISSN: 1362-4962

    Many bacterial adaptive responses to changes in growth conditions due to biotic and abiotic factors involve reprogramming of gene expression at the transcription level. The bacterial RNA polymerase (RNAP), which catalyzes transcription, can thus be considered as the major mediator of cellular adaptive strategies. But how do bacteria respond if a stress factor directly compromises the activity of the RNAP? We used a phage-derived small protein to specifically perturb bacterial RNAP activity in exponentially growing Escherichia coli. Using cytological profiling, tracking RNAP behavior at single-molecule level and transcriptome analysis, we reveal that adaptation to conditions that directly perturb bacterial RNAP performance can result in a biphasic growth behavior and thereby confer the ‘adapted’ bacterial cells an enhanced ability to tolerate diverse antibacterial stresses. The results imply that while synthetic transcriptional rewiring may confer bacteria with the intended desirable properties, such approaches may also collaterally allow them to acquire undesirable traits.

  • Journal article
    rouse S, hawthorne, berry, Chorev D, Ionescu S, Lambert S, Stylianou F, Ewert W, Mackie U, Morgan, Otzen D, Herbst F-A, Nielsen P, Dueholm M, Bayley H, Robinson C, Hare S, Matthews Set al., 2017,

    A new class of hybrid secretion system is employed in 2 Pseudomonas amyloid biogenesis

    , Nature Communications, Vol: 8, ISSN: 2041-1723

    Gram-negative bacteria possess specialised biogenesis machineries that facilitate the export of amyloid subunits for construction of a biofilm matrix. The secretion of bacterial functional amyloid requires a bespoke outer-membrane protein channel through which unfolded amyloid substrates are translocated. Here, we combine X-ray crystallography, native mass spectrometry, single-channel electrical recording, molecular simulations and circular dichroism measurements to provide high-resolution structural insight into the functional amyloid transporter from Pseudomonas, FapF. FapF forms a trimer of gated β-barrel channels in which opening is regulated by a helical plug connected to an extended coil-coiled platform spanning the bacterial periplasm. Although FapF represents a unique type of secretion system, it shares mechanistic features with a diverse range of peptide translocation systems. Our findings highlight alternative strategies for handling and export of amyloid protein sequences.

  • Journal article
    Jennings E, Thurston TLM, Holden DW, 2017,

    Salmonella SPI-2 Type III Secretion System Effectors: Molecular Mechanisms And Physiological Consequences

    , CELL HOST & MICROBE, Vol: 22, Pages: 217-231, ISSN: 1931-3128
  • Journal article
    Furniss RCD, Clements A, 2017,

    Regulation of the Locus of Enterocyte Effacement in Attaching and Effacing Pathogens.

    , Journal of Bacteriology, Vol: 200, ISSN: 0021-9193

    Attaching and Effacing (AE) pathogens colonise the gut mucosa using a Type Three Secretion System (T3SS) and a suite of effector proteins. The Locus of Enterocyte Effacement (LEE) is the defining genetic feature of the AE pathogens, encoding the T3SS and the core effector proteins necessary for pathogenesis. Extensive research has revealed a complex regulatory network that senses and responds to a myriad of host and microbiota-derived signals in the infected gut to control transcription of the LEE. These signals include microbiota-liberated sugars and metabolites in the gut lumen, molecular oxygen at the gut epithelium and host hormones. Recent research has revealed that AE pathogens also perceive physical signals, such as attachment to the epithelium, and that the act of effector translocation remodels gene expression in infecting bacteria. In this review we summarise our knowledge to date and present an integrated view of how chemical, geographical and physical cues regulate the virulence program of AE pathogens during infection.

  • Journal article
    Davies SK, Fearn S, Allsopp LP, Harrison F, Ware E, Diggle SP, Filloux A, McPhail DS, Bundy Jet al., 2017,

    Visualizing Antimicrobials in BacterialBiofilms: Three-Dimensional BiochemicalImaging Using TOF-SIMS

    , mSphere, Vol: 2, ISSN: 2379-5042

    Bacterial biofilms are groups of bacteria that exist within a self-produced extracellular matrix, adhering to each other and usually to a surface. They grow on medical equipment and inserts such as catheters and are responsible for many persistent infections throughout the body, as they can have high resistance to many antimicrobials. Pseudomonas aeruginosa is an opportunistic pathogen that can cause both acute and chronic infections and is used as a model for research into biofilms. Direct biochemical methods of imaging of molecules in bacterial biofilms are of high value in gaining a better understanding of the fundamental biology of biofilms and biochemical gradients within them. Time of flight–secondary-ion mass spectrometry (TOF-SIMS) is one approach, which combines relatively high spatial resolution and sensitivity and can perform depth profiling analysis. It has been used to analyze bacterial biofilms but has not yet been used to study the distribution of antimicrobials (including antibiotics and the antimicrobial metal gallium) within biofilms. Here we compared two methods of imaging of the interior structure of P. aeruginosa in biological samples using TOF-SIMS, looking at both antimicrobials and endogenous biochemicals: cryosectioning of tissue samples and depth profiling to give pseudo-three-dimensional (pseudo-3D) images. The sample types included both simple biofilms grown on glass slides and bacteria growing in tissues in an ex vivo pig lung model. The two techniques for the 3D imaging of biofilms are potentially valuable complementary tools for analyzing bacterial infection.

  • Journal article
    du Plessis J, Cloete R, Burchell L, Sarkar P, Warren RM, Christoffels A, Wigneshweraraj S, Sampson SLet al., 2017,

    Exploring the potential of T7 bacteriophage protein Gp2 as a novel inhibitor of mycobacterial RNA polymerase

    , Tuberculosis, Vol: 106, Pages: 82-90, ISSN: 1472-9792

    Over the past six decades, there has been a decline in novel therapies to treat tuberculosis, while the causative agent of this disease has become increasingly resistant to current treatment regimens. Bacteriophages (phages) are able to kill bacterial cells and understanding this process could lead to novel insights for the treatment of mycobacterial infections. Phages inhibit bacterial gene transcription through phage-encoded proteins which bind to RNA polymerase (RNAP), thereby preventing bacterial transcription. Gp2, a T7 phage protein which binds to the beta prime (β′) subunit of RNAP in Escherichia coli, has been well characterized in this regard. Here, we aimed to determine whether Gp2 is able to inhibit RNAP in Mycobacterium tuberculosis as this may provide new possibilities for inhibiting the growth of this deadly pathogen. Results from an electrophoretic mobility shift assay and in vitro transcription assay revealed that Gp2 binds to mycobacterial RNAP and inhibits transcription; however to a much lesser degree than in E. coli. To further understand the molecular basis of these results, a series of in silico techniques were used to assess the interaction between mycobacterial RNAP and Gp2, providing valuable insight into the characteristics of this protein-protein interaction.

  • Journal article
    Allsopp LP, Wood TE, Howard SA, Maggiorelli F, Nolan LM, Wettstadt S, Filloux Aet al., 2017,

    RsmA and AmrZ orchestrate the assembly of all three type VI secretion systems in Pseudomonas aeruginosa

    , Proceedings of the National Academy of Sciences of the United States of America, Vol: 114, Pages: 7707-7712, ISSN: 1091-6490

    The type VI secretion system (T6SS) is a weapon of bacterial warfare and host cell subversion. The Gram-negative pathogen Pseudomonas aeruginosa has three T6SSs involved in colonization, competition, and full virulence. H1-T6SS is a molecular gun firing seven toxins, Tse1–Tse7, challenging survival of other bacteria and helping P. aeruginosa to prevail in specific niches. The H1-T6SS characterization was facilitated through studying a P. aeruginosa strain lacking the RetS sensor, which has a fully active H1-T6SS, in contrast to the parent. However, study of H2-T6SS and H3-T6SS has been neglected because of a poor understanding of the associated regulatory network. Here we performed a screen to identify H2-T6SS and H3-T6SS regulatory elements and found that the posttranscriptional regulator RsmA imposes a concerted repression on all three T6SS clusters. A higher level of complexity could be observed as we identified a transcriptional regulator, AmrZ, which acts as a negative regulator of H2-T6SS. Overall, although the level of T6SS transcripts is fine-tuned by AmrZ, all T6SS mRNAs are silenced by RsmA. We expanded this concept of global control by RsmA to VgrG spike and T6SS toxin transcripts whose genes are scattered on the chromosome. These observations triggered the characterization of a suite of H2-T6SS toxins and their implication in direct bacterial competition. Our study thus unveils a central mechanism that modulates the deployment of all T6SS weapons that may be simultaneously produced within a single cell.

  • Journal article
    Mazon-Moya MJ, Willis AR, Torraca V, Boucontet L, Shenoy AR, Colucci-Guyon E, Mostowy Set al., 2017,

    Septins restrict inflammation and protect zebrafish larvae from Shigella infection

    , PLoS Pathogens, Vol: 13, ISSN: 1553-7366

    Shigella flexneri, a Gram-negative enteroinvasive pathogen, causes inflammatory destruction of the human intestinal epithelium. Infection by S. flexneri has been well-studied in vitro and is a paradigm for bacterial interactions with the host immune system. Recent work has revealed that components of the cytoskeleton have important functions in innate immunity and inflammation control. Septins, highly conserved cytoskeletal proteins, have emerged as key players in innate immunity to bacterial infection, yet septin function in vivo is poorly understood. Here, we use S. flexneri infection of zebrafish (Danio rerio) larvae to study in vivo the role of septins in inflammation and infection control. We found that depletion of Sept15 or Sept7b, zebrafish orthologs of human SEPT7, significantly increased host susceptibility to bacterial infection. Live-cell imaging of Sept15-depleted larvae revealed increasing bacterial burdens and a failure of neutrophils to control infection. Strikingly, Sept15-depleted larvae present significantly increased activity of Caspase-1 and more cell death upon S. flexneri infection. Dampening of the inflammatory response with anakinra, an antagonist of interleukin-1 receptor (IL-1R), counteracts Sept15 deficiency in vivo by protecting zebrafish from hyper-inflammation and S. flexneri infection. These findings highlight a new role for septins in host defence against bacterial infection, and suggest that septin dysfunction may be an underlying factor in cases of hyper-inflammation.

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