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  • 1.
    Boamah, David
    et al.
    Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States.
    Gilmore, Michael C.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bourget, Sarah
    Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States.
    Ghosh, Anushka
    Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States.
    Hossain, Mohammad J.
    Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States.
    Vogel, Joseph P.
    Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    O'Connor, Tamara J.
    Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, United States.
    Peptidoglycan deacetylation controls type IV secretion and the intracellular survival of the bacterial pathogen Legionella pneumophila2023In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, no 23, article id  e2119658120Article in journal (Refereed)
    Abstract [en]

    Peptidoglycan is a critical component of the bacteria cell envelope. Remodeling of the peptidoglycan is required for numerous essential cellular processes and has been linked to bacterial pathogenesis. Peptidoglycan deacetylases that remove the acetyl group of the N-acetylglucosamine (NAG) subunit protect bacterial pathogens from immune recognition and digestive enzymes secreted at the site of infection. However, the full extent of this modification on bacterial physiology and pathogenesis is not known. Here, we identify a polysaccharide deacetylase of the intracellular bacterial pathogen Legionella pneumophila and define a two-tiered role for this enzyme in Legionella pathogenesis. First, NAG deacetylation is important for the proper localization and function of the Type IVb secretion system, linking peptidoglycan editing to the modulation of host cellular processes through the action of secreted virulence factors. As a consequence, the Legionella vacuole mis-traffics along the endocytic pathway to the lysosome, preventing the formation of a replication permissive compartment. Second, within the lysosome, the inability to deacetylate the peptidoglycan renders the bacteria more sensitive to lysozyme-mediated degradation, resulting in increased bacterial death. Thus, the ability to deacetylate NAG is important for bacteria to persist within host cells and in turn, Legionella virulence. Collectively, these results expand the function of peptidoglycan deacetylases in bacteria, linking peptidoglycan editing, Type IV secretion, and the intracellular fate of a bacterial pathogen.

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  • 2.
    Chan, Helena
    et al.
    Australian Institute for Microbiology and Infection, University of Technology Sydneygrid.117476.2 (UTS), Sydney, Australia.
    Taib, Najwa
    Department of Microbiology, Unit Evolutionary Biology of the Microbial Cell, Paris, France; Hub Bioinformatics and Biostatistics, Department of Computational Biology, USR 3756 CNRS, Paris, France.
    Gilmore, Michael C.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Mohamed, Ahmed M T
    Australian Institute for Microbiology and Infection, University of Technology Sydneygrid.117476.2 (UTS), Sydney, Australia.
    Hanna, Kieran
    Australian Institute for Microbiology and Infection, University of Technology Sydneygrid.117476.2 (UTS), Sydney, Australia.
    Luhur, Johana
    Australian Institute for Microbiology and Infection, University of Technology Sydneygrid.117476.2 (UTS), Sydney, Australia.
    Nguyen, Hieu
    Australian Institute for Microbiology and Infection, University of Technology Sydneygrid.117476.2 (UTS), Sydney, Australia.
    Hafiz, Elham
    Australian Institute for Microbiology and Infection, University of Technology Sydneygrid.117476.2 (UTS), Sydney, Australia.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gribaldo, Simonetta
    Department of Microbiology, Unit Evolutionary Biology of the Microbial Cell, Paris, France; Hub Bioinformatics and Biostatistics, Department of Computational Biology, USR 3756 CNRS, Paris, France.
    Rudner, David
    Department of Microbiology, MA, Boston, United States.
    Rodrigues, Christopher D A
    School of Life Sciences, University of Warwickgrid.7372.1, Coventry, United Kingdom.
    Genetic screens identify additional genes implicated in envelope remodeling during the engulfment stage of bacillus subtilis sporulation2022In: mBio, ISSN 2161-2129, E-ISSN 2150-7511, Vol. 13, no 5, article id e0173222Article in journal (Refereed)
    Abstract [en]

    During bacterial endospore formation, the developing spore is internalized into the mother cell through a phagocytic-like process called engulfment, which involves synthesis and hydrolysis of peptidoglycan. Engulfment peptidoglycan hydrolysis requires the widely conserved and well-characterized DMP complex, composed of SpoIID, SpoIIM, and SpoIIP. In contrast, although peptidoglycan synthesis has been implicated in engulfment, the protein players involved are less well defined. The widely conserved SpoIIIAH-SpoIIQ interaction is also required for engulfment efficiency, functioning like a ratchet to promote membrane migration around the forespore. Here, we screened for additional factors required for engulfment using transposon sequencing in Bacillus subtilis mutants with mild engulfment defects. We discovered that YrvJ, a peptidoglycan hydrolase, and the MurA paralog MurAB, involved in peptidoglycan precursor synthesis, are required for efficient engulfment. Cytological analyses suggest that both factors are important for engulfment when the DMP complex is compromised and that MurAB is additionally required when the SpoIIIAH-SpoIIQ ratchet is abolished. Interestingly, despite the importance of MurAB for sporulation in B. subtilis, phylogenetic analyses of MurA paralogs indicate that there is no correlation between sporulation and the number of MurA paralogs and further reveal the existence of a third MurA paralog, MurAC, within the Firmicutes. Collectively, our studies identify two new factors that are required for efficient envelop remodeling during sporulation and highlight the importance of peptidoglycan precursor synthesis for efficient engulfment in B. subtilis and likely other endospore-forming bacteria. IMPORTANCE In bacteria, cell envelope remodeling is critical for cell growth and division. This is also the case during the development of bacteria into highly resistant endospores (spores), known as sporulation. During sporulation, the developing spore becomes internalized inside the mother cell through a phagocytic-like process called engulfment, which is essential to form the cell envelope of the spore. Engulfment involves both the synthesis and hydrolysis of peptidoglycan and the stabilization of migrating membranes around the developing spore. Importantly, although peptidoglycan synthesis has been implicated during engulfment, the specific genes that contribute to this molecular element of engulfment have remained unclear. Our study identifies two new factors that are required for efficient envelope remodeling during engulfment and emphasizes the importance of peptidoglycan precursor synthesis for efficient engulfment in the model organism Bacillus subtilis and likely other endospore-forming bacteria. Finally, our work highlights the power of synthetic screens to reveal additional genes that contribute to essential processes during sporulation.

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  • 3.
    Delerue, Thomas
    et al.
    Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Anantharaman, Vivek
    National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, MD, Bethesda, United States.
    Gilmore, Michael C.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Popham, David L.
    Department of Biological Sciences, Virginia Tech, VA, Blacksburg, United States.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Aravind, L.
    National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, MD, Bethesda, United States.
    Ramamurthi, Kumaran S.
    Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, MD, Bethesda, United States.
    Bacterial developmental checkpoint that directly monitors cell surface morphogenesis2022In: Developmental Cell, ISSN 1534-5807, E-ISSN 1878-1551, Vol. 57, no 3, p. 344-360Article in journal (Refereed)
    Abstract [en]

    Bacillus subtilis spores are encased in two concentric shells: an outer proteinaceous “coat” and an inner peptidoglycan “cortex,” separated by a membrane. Cortex assembly depends on coat assembly initiation, but how cells achieve this coordination across the membrane is unclear. Here, we report that the protein SpoVID monitors the polymerization state of the coat basement layer via an extension to a functional intracellular LysM domain that arrests sporulation when coat assembly is initiated improperly. Whereas extracellular LysM domains bind mature peptidoglycan, SpoVID LysM binds to the membrane-bound lipid II peptidoglycan precursor. We propose that improper coat assembly exposes the SpoVID LysM domain, which then sequesters lipid II and prevents cortex assembly. SpoVID defines a widespread group of firmicute proteins with a characteristic N-terminal domain and C-terminal peptidoglycan-binding domains that might combine coat and cortex assembly roles to mediate a developmental checkpoint linking the morphogenesis of two spatially separated supramolecular structures.

  • 4.
    Gilmore, Michael C.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Studies on cell wall recycling and modification in Gram-negative bacteria2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The bacterial cell wall is made from peptidoglycan (PG), a heteropolymer which forms a bag-like exoskeleton that envelopes the cell. PG is constantly remodelled during growth and division, and in response to environmental stimuli. Decades of study of this process have focused largely on a select few model organisms, leaving its diversity poorly understood. In this thesis, I present studies on different aspects of PG recycling and modification in several Gram-negative models, with a particular focus on the plant pathogen Agrobacterium tumefaciens, a model of the Hyphomicrobiales group of the Alphaproteobacteria which includes several species of medical and environmental interest. It is shown that A. tumefaciens encodes a novel PG transporter, which is vital for cell wall integrity and resistance to β- lactam antibiotics, and widely conserved in the Hyphomicrobiales and Rhodobacterales orders. Growth defects caused by the loss of the transporter are suppressed by mutations in a novel glycopolymer, which is hypothesized to play a role in sequestering metal ions and thereby lowering periplasmic oxidative stress. Next, in collaboration, it is shown that PG recycling in the best studied model, Escherichia coli, is more complicated than previously thought. Rather than depending mostly on the MFS-family transporter AmpG, E. coli uses an ABC transporter, MppA-OppBCDF or AmpG depending on the growth phase and conditions. Finally, two studies on modification of PG by deacetylation are presented. First, A. tumefaciens is shown to encode a novel anhydroMurNAc deacetylase, which specifically deacetylates the PG chain termini. Then, it is shown that the causative agent of Legionnaires’ disease, Legionella pneumophila, depends on deacetylation of its PG during infection for defence against host lysozyme and correct polar placement of its type IV secretion system. 

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  • 5.
    Gilmore, Michael C.
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Peptidoglycan recycling mediated by an ABC transporter in the plant pathogen Agrobacterium tumefaciens2022In: Nature Communications, E-ISSN 2041-1723, Vol. 13, no 1, article id 7927Article in journal (Refereed)
    Abstract [en]

    During growth and division, the bacterial cell wall peptidoglycan (PG) is remodelled, resulting in the liberation of PG muropeptides which are typically reinternalized and recycled. Bacteria belonging to the Rhizobiales and Rhodobacterales orders of the Alphaproteobacteria lack the muropeptide transporter AmpG, despite having other key PG recycling enzymes. Here, we show that an alternative transporter, YejBEF-YepA, takes over this role in the Rhizobiales phytopathogen Agrobacterium tumefaciens. Muropeptide import by YejBEF-YepA governs expression of the β-lactamase AmpC in A. tumefaciens, contributing to β-lactam resistance. However, we show that the absence of YejBEF-YepA causes severe cell wall defects that go far beyond lowered AmpC activity. Thus, contrary to previously established Gram-negative models, PG recycling is vital for cell wall integrity in A. tumefaciens. YepA is widespread in the Rhizobiales and Rhodobacterales, suggesting that YejBEF-YepA-mediated PG recycling could represent an important but overlooked aspect of cell wall biology in these bacteria.

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  • 6.
    Gilmore, Michael C.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Mateus, André
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    A metal ion-sequestering polymer protects the Agrobacterium tumefaciens periplasm from oxidative damageManuscript (preprint) (Other academic)
  • 7.
    Gilmore, Michael C.
    et al.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Yadav, Akhilesh K.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Academy of Scientific and Innovative Research (AcSIR), Uttar Pradesh, Ghaziabad, India; Regulatory Toxicology Group, CSIR-Indian Institute of Toxicology Research (CSIR-IITR), Uttar Pradesh, Lucknow, India.
    Espaillat, Akbar
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Gust, Andrea A.
    Department of Plant Biochemistry, Center of Plant Molecular Biology (ZMBP), Eberhard-Karls-University of Tübingen, Tübingen, Germany.
    Williams, Michelle A.
    Division of Biological Sciences, University of Missouri-Columbia, MO, Columbia, United States.
    Brown, Pamela J.B.
    Division of Biological Sciences, University of Missouri-Columbia, MO, Columbia, United States.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    A peptidoglycan N-deacetylase specific for anhydroMurNAc chain termini in Agrobacterium tumefaciens2024In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 300, no 2, article id 105611Article in journal (Refereed)
    Abstract [en]

    During growth, bacteria remodel and recycle their peptidoglycan (PG). A key family of PG-degrading enzymes is the lytic transglycosylases, which produce anhydromuropeptides, a modification that caps the PG chains and contributes to bacterial virulence. Previously, it was reported that the polar-growing Gram-negative plant pathogen Agrobacterium tumefaciens lacks anhydromuropeptides. Here, we report the identification of an enzyme, MdaA (MurNAc deacetylase A), which specifically removes the acetyl group from anhydromuropeptide chain termini in A. tumefaciens, resolving this apparent anomaly. A. tumefaciens lacking MdaA accumulates canonical anhydromuropeptides, whereas MdaA was able to deacetylate anhydro-N-acetyl muramic acid in purified sacculi that lack this modification. As for other PG deacetylases, MdaA belongs to the CE4 family of carbohydrate esterases but harbors an unusual Cys residue in its active site. MdaA is conserved in other polar-growing bacteria, suggesting a possible link between PG chain terminus deacetylation and polar growth.

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  • 8.
    Simpson, Brent W.
    et al.
    Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, GA, Athens, United States.
    Gilmore, Michael C.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    McLean, Amanda Briann
    Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, GA, Athens, United States.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Trent, M. Stephen
    Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, GA, Athens, United States; Department of Microbiology, College of Arts and Sciences, University of Georgia, GA, Athens, United States.
    Escherichia coli CadB is capable of promiscuously transporting muropeptides and contributing to peptidoglycan recycling2024In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 206, no 1, article id e0036923Article in journal (Refereed)
    Abstract [en]

    The bacterial peptidoglycan (PG) cell wall is remodeled during growth and division, releasing fragments called muropeptides. Muropeptides can be internalized and reused in a process called PG recycling. Escherichia coli is highly devoted to recycling muropeptides and is known to have at least two transporters, AmpG and OppBCDF, that import them into the cytoplasm. While studying mutants lacking AmpG, we unintentionally isolated mutations that led to the altered expression of a third transporter, CadB. CadB is normally upregulated under acidic pH conditions and is an antiporter for lysine and cadaverine. Here, we explored if CadB was altering PG recycling to assist in the absence of AmpG. Surprisingly, CadB overexpression was able to restore PG recycling when both AmpG and OppBCDF were absent. CadB was found to import freed PG peptides, a subpopulation of muropeptides, through a promiscuous activity. Altogether, our data support that CadB is a third transporter capable of contributing to PG recycling.

  • 9.
    Simpson, Brent W.
    et al.
    Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, United States.
    Gilmore, Michael C.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    McLean, Amanda Briann
    Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, United States.
    Cava, Felipe
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Trent, M. Stephen
    Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, United States; Department of Microbiology, College of Art and Sciences, University of Georgia, Athens, United States.
    Escherichia coli utilizes multiple peptidoglycan recycling permeases with distinct strategies of recycling2023In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 120, no 44, article id e2308940120Article in journal (Refereed)
    Abstract [en]

    Bacteria produce a structural layer of peptidoglycan (PG) that enforces cell shape, resists turgor pressure, and protects the cell. As bacteria grow and divide, the existing layer of PG is remodeled and PG fragments are released. Enterics such as Escherichia coli go to great lengths to internalize and reutilize PG fragments. E. coli is estimated to break down one-third of its cell wall, yet only loses ~0 to 5% of meso-diaminopimelic acid, a PG-specific amino acid, per generation. Two transporters were identified early on to possibly be the primary permease that facilitates PG fragment recycling, i) AmpG and ii) the Opp ATP binding cassette transporter in conjunction with a PG-specific periplasmic binding protein, MppA. The contribution of each transporter to PG recycling has been debated. Here, we have found that AmpG and MppA/Opp are differentially regulated by carbon source and growth phase. In addition, MppA/Opp is uniquely capable of high-affinity scavenging of muropeptides from growth media, demonstrating that AmpG and MppA/Opp allow for different strategies of recycling PG fragments. Altogether, this work clarifies environmental contexts under which E. coli utilizes distinct permeases for PG recycling and explores how scavenging by MppA/Opp could be beneficial in mixed communities.

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