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  • Journal article
    Macé K, Vadakkepat AK, Redzej A, Lukoyanova N, Oomen C, Braun N, Ukleja M, Lu F, Dias da Costa T, Orlova EV, Baker D, Cong Q, Waksman Get al., 2022,

    Cryo-EM structure of a type IV secretion system

    , Nature, Vol: 607, ISSN: 0028-0836

    Bacterial conjugation is the fundamental process of unidirectional transfer of DNAs, often plasmid DNAs, from a donor cell to a recipient cell1. It is the primary means by which antibiotic resistance genes spread among bacterial populations2,3. In Gram-negative bacteria, conjugation is mediated by a large transport apparatus-the conjugative type IV secretion system (T4SS)-produced by the donor cell and embedded in both its outer and inner membranes. The T4SS also elaborates a long extracellular filament-the conjugative pilus-that is essential for DNA transfer4,5. Here we present a high-resolution cryo-electron microscopy (cryo-EM) structure of a 2.8 megadalton T4SS complex composed of 92 polypeptides representing 8 of the 10 essential T4SS components involved in pilus biogenesis. We added the two remaining components to the structural model using co-evolution analysis of protein interfaces, to enable the reconstitution of the entire system including the pilus. This structure describes the exceptionally large protein-protein interaction network required to assemble the many components that constitute a T4SS and provides insights on the unique mechanism by which they elaborate pili.

  • Journal article
    Gerovasili V, Shah A, Singanayagam A, George PM, Njafuh R, Prendecki M, Carby M, Willicombe M, Kelleher P, Reed Aet al., 2022,

    Impaired humoral and cellular responses to COVID-19 vaccine in heart and lung transplant recipients

    , American Journal of Respiratory and Critical Care Medicine, Vol: 205, Pages: 1476-1479, ISSN: 1073-449X
  • Journal article
    Faiez TS, Singanayagam A, 2022,

    Down to a T: The Functional Importance of Lymphopenia in Severe COVID-19

  • Journal article
    Low WW, Wong J, Beltran L, Seddon C, David S, Kwong H-S, Bizeau T, Wang F, Pena A, Costa TRD, Pham B, Chen M, Egelman E, Beis K, Frankel Get al., 2022,

    Mating pair stabilization mediates bacterial conjugation species specificity

    , Nature Microbiology, Vol: 7, Pages: 1016-1027, ISSN: 2058-5276

    Bacterial conjugation mediates contact-dependent transfer of DNA from donor to recipient bacteria, thus facilitating thespread of virulence and resistance plasmids. Here we describe how variants of the plasmid-encoded donor outer membrane(OM) protein TraN cooperate with distinct OM receptors in recipients to mediate mating pair stabilization and efficient DNAtransfer. We show that TraN from the plasmids pKpQIL (Klebsiella pneumoniae), R100-1 (Shigella flexneri) and pSLT (SalmonellaTyphimurium), and the prototypical F plasmid (Escherichia coli) interact with OmpK36, OmpW and OmpA, respectively.Cryo-EM analysis revealed that TraN pKpQIL interacts with OmpK36 through the insertion of a β-hairpin in the tip of TraN intoa monomer of the OmpK36 trimer. Combining bioinformatic analysis with AlphaFold structural predictions, we identified afourth TraN structural variant that mediates mating pair stabilization by binding OmpF. Accordingly, we devised a classifica-tion scheme for TraN homologues on the basis of structural similarity and their associated receptors: TraNα (OmpW), TraNβ(OmpK36), TraNγ (OmpA), TraNδ (OmpF). These TraN-OM receptor pairings have real-world implications as they reflect thedistribution of resistance plasmids within clinical Enterobacteriaceae isolates, demonstrating the importance of mating pairstabilization in mediating conjugation species specificity. These findings will allow us to predict the distribution of emergingresistance plasmids in high-risk bacterial pathogens.

  • Journal article
    Bikmetov D, Hall AMJ, Livenskyi A, Gollan B, Ovchinnikov S, Gilep K, Kim JY, Larrouy-Maumus G, Zgoda V, Borukhov S, Severinov K, Helaine S, Dubiley Set al., 2022,

    GNAT toxins evolve toward narrow tRNA target specificities

    , NUCLEIC ACIDS RESEARCH, Vol: 50, Pages: 5807-5817, ISSN: 0305-1048
  • Journal article
    Higginson EE, Nkeze J, Permala-Booth J, Kasumba IN, Lagos R, Hormazabal JC, Byrne A, Frankel G, Levine MM, Tennant SMet al., 2022,

    Detection of Salmonella Typhi in Bile by Quantitative Real-Time PCR

    , MICROBIOLOGY SPECTRUM, Vol: 10, ISSN: 2165-0497
  • Journal article
    Sanchez Garrido J, Ruano-Gallego D, Choudhary JS, Frankel Get al., 2022,

    The type III secretion system effector network hypothesis

    , Trends in Microbiology, Vol: 30, Pages: 524-533, ISSN: 0966-842X

    Type III secretion system (T3SS) effectors are key virulence factors that underpin the infection strategy of many clinically important Gram-negative pathogens, including Salmonella enterica, Shigella spp, enteropathogenic and enterohaemorrhagic Escherichia coli and their murine equivalent, Citrobacter rodentium. The cellular processes or proteins targeted by the effectors can be common to multiple pathogens or pathogen-specific. The main approach to understanding T3SS-mediated pathogenesis has been to determine the contribution of one effector at a time, with the aim to piece together individual functions and unveil infection mechanisms. However, in contrast to this prevailing approach, simultaneous deletion of multiple effectors revealed that they function as an interconnected network in vivo, uncoveringeffector co-dependency and context-dependent effector essentiality. This paradigm shift in T3SS biology is at the heart of this opinion.

  • Journal article
    Lockwood DC, Amin H, Costa TRD, Schroeder GNet al., 2022,

    The Legionella pneumophila Dot/Icm type IV secretion system and its effectors

    , Microbiology, Vol: 168, ISSN: 1350-0872

    To prevail in the interaction with eukaryotic hosts, many bacterial pathogens use protein secretion systems to release virulence factors at the host–pathogen interface and/or deliver them directly into host cells. An outstanding example of the complexity and sophistication of secretion systems and the diversity of their protein substrates, effectors, is the Defective in organelle trafficking/Intracellular multiplication (Dot/Icm) Type IVB secretion system (T4BSS) of Legionella pneumophila and related species. Legionella species are facultative intracellular pathogens of environmental protozoa and opportunistic human respiratory pathogens. The Dot/Icm T4BSS translocates an exceptionally large number of effectors, more than 300 per L. pneumophila strain, and is essential for evasion of phagolysosomal degradation and exploitation of protozoa and human macrophages as replicative niches. Recent technological advancements in the imaging of large protein complexes have provided new insight into the architecture of the T4BSS and allowed us to propose models for the transport mechanism. At the same time, significant progress has been made in assigning functions to about a third of L. pneumophila effectors, discovering unprecedented new enzymatic activities and concepts of host subversion. In this review, we describe the current knowledge of the workings of the Dot/Icm T4BSS machinery and provide an overview of the activities and functions of the to-date characterized effectors in the interaction of L. pneumophila with host cells.

  • Journal article
    Webberley TS, Masetti G, Bevan RJ, Kerry-Smith J, Jack AA, Michael DR, Thomas S, Glymenaki M, Li J, McDonald JAK, John D, Morgan JE, Marchesi JR, Good MA, Plummer SF, Hughes TRet al., 2022,

    The Impact of Probiotic Supplementation on Cognitive, Pathological and Metabolic Markers in a Transgenic Mouse Model of Alzheimer's Disease

  • Journal article
    Chee Wezen X, Chandran A, Eapen RS, Waters E, Bricio-Moreno L, Tosi T, Dolan S, Millership C, Kadioglu A, Gründling A, Itzhaki LS, Welch M, Rahman Tet al., 2022,

    Structure-based discovery of lipoteichoic acid synthase inhibitors.

    , Journal of Chemical Information and Modeling, Vol: 62, Pages: 2586-2599, ISSN: 1549-9596

    Lipoteichoic acid synthase (LtaS) is a key enzyme for the cell wall biosynthesis of Gram-positive bacteria. Gram-positive bacteria that lack lipoteichoic acid (LTA) exhibit impaired cell division and growth defects. Thus, LtaS appears to be an attractive antimicrobial target. The pharmacology around LtaS remains largely unexplored with only two small-molecule LtaS inhibitors reported, namely "compound 1771" and the Congo red dye. Structure-based drug discovery efforts against LtaS remain unattempted due to the lack of an inhibitor-bound structure of LtaS. To address this, we combined the use of a molecular docking technique with molecular dynamics (MD) simulations to model a plausible binding mode of compound 1771 to the extracellular catalytic domain of LtaS (eLtaS). The model was validated using alanine mutagenesis studies combined with isothermal titration calorimetry. Additionally, lead optimization driven by our computational model resulted in an improved version of compound 1771, namely, compound 4 which showed greater affinity for binding to eLtaS than compound 1771 in biophysical assays. Compound 4 reduced LTA production in S. aureus dose-dependently, induced aberrant morphology as seen for LTA-deficient bacteria, and significantly reduced bacteria titers in the lung of mice infected with S. aureus. Analysis of our MD simulation trajectories revealed the possible formation of a transient cryptic pocket in eLtaS. Virtual screening (VS) against the cryptic pocket led to the identification of a new class of inhibitors that could potentiate β-lactams against methicillin-resistant S. aureus. Our overall workflow and data should encourage further drug design campaign against LtaS. Finally, our work reinforces the importance of considering protein conformational flexibility to a successful VS endeavor.

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