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  • Journal article
    Harnagel A, Quezada LL, Park SW, Baranowski C, Kieser K, Jiang X, Roberts J, Vaubourgeix J, Yang A, Nelson B, Fay A, Rubin E, Ehrt S, Nathan C, Lupoli TJet al., 2021,

    Nonredundant functions of <i>Mycobacterium tuberculosis</i> chaperones promote survival under stress

    , MOLECULAR MICROBIOLOGY, Vol: 115, Pages: 272-289, ISSN: 0950-382X
  • Journal article
    Moldoveanu AL, Rycroft JA, Helaine S, 2021,

    Impact of bacterial persisters on their host

    , CURRENT OPINION IN MICROBIOLOGY, Vol: 59, Pages: 65-71, ISSN: 1369-5274
    • Cite
    • Citations: 20
  • Journal article
    Brown RL, Larkinson MLY, Clarke TB, 2021,

    Immunological design of commensal communities to treat intestinal infection and inflammation

    , PLoS Pathogens, Vol: 17, ISSN: 1553-7366

    The immunological impact of individual commensal species within the microbiota is poorly understood limiting the use of commensals to treat disease. Here, we systematically profile the immunological fingerprint of commensals from the major phyla in the human intestine (Actinobacteria, Bacteroidetes, Firmicutes and Proteobacteria) to reveal taxonomic patterns in immune activation and use this information to rationally design commensal communities to enhance antibacterial defenses and combat intestinal inflammation. We reveal that Bacteroidetes and Firmicutes have distinct effects on intestinal immunity by differentially inducing primary and secondary response genes. Within these phyla, the immunostimulatory capacity of commensals from the Bacteroidia class (Bacteroidetes phyla) reflects their robustness of TLR4 activation and Bacteroidia communities rely solely on this receptor for their effects on intestinal immunity. By contrast, within the Clostridia class (Firmicutes phyla) it reflects the degree of TLR2 and TLR4 activation, and communities of Clostridia signal via both of these receptors to exert their effects on intestinal immunity. By analyzing the receptors, intracellular signaling components and transcription factors that are engaged by different commensal species, we identify canonical NF-κB signaling as a critical rheostat which grades the degree of immune stimulation commensals elicit. Guided by this immunological analysis, we constructed a cross-phylum consortium of commensals (Bacteroides uniformis, Bacteroides ovatus, Peptostreptococcus anaerobius and Clostridium histolyticum) which enhances innate TLR, IL6 and macrophages-dependent defenses against intestinal colonization by vancomycin resistant Enterococci, and fortifies mucosal barrier function during pathological intestinal inflammation through the same pathway. Critically, the setpoint of intestinal immunity established by this consortium is calibrated by canonical NF-κB signaling. Thu
  • Journal article
    Zheng W, Peña A, Ilangovan A, Clark JN-B, Frankel G, Egelman EH, Costa TRDet al., 2021,

    Cryoelectron-microscopy structure of the enteropathogenic Escherichia coli type III secretion system EspA filament

    , Proceedings of the National Academy of Sciences of USA, Vol: 118, ISSN: 0027-8424

    Enteropathogenic Escherichia coli (EPEC) and enterohemorrhagic Escherichia coli (EHEC) utilize a macromolecular type III secretion system (T3SS) to inject effector proteins into eukaryotic cells. This apparatus spans the inner and outer bacterial membranes and includes a helical needle protruding into the extracellular space. Thus far observed only in EPEC and EHEC and not found in other pathogenic Gram-negative bacteria that have a T3SS is an additional helical filament made by the EspA protein that forms a long extension to the needle, mediating both attachment to eukaryotic cells and transport of effector proteins through the intestinal mucus layer. Here, we present the structure of the EspA filament from EPEC at 3.4 Å resolution. The structure reveals that the EspA filament is a right-handed 1-start helical assembly with a conserved lumen architecture with respect to the needle to ensure the seamless transport of unfolded cargos en route to the target cell. This functional conservation is despite the fact that there is little apparent overall conservation at the level of sequence or structure with the needle. We also unveil the molecular details of the immunodominant EspA epitope that can now be exploited for the rational design of epitope display systems.
  • Journal article
    Zhang K, Raju C, Zhong W, Pethe K, Gründling A, Chan-Park MBet al., 2021,

    Cationic glycosylated block Co-β-peptide acts on the cell wall of gram-positive bacteria as anti-biofilm agents

    , ACS Applied Bio Materials, Vol: 4, Pages: 3749-3761, ISSN: 2576-6422

    Antimicrobial resistance is a global threat. In addition to the emergence of resistance to last resort drugs, bacteria escape antibiotics killing by forming complex biofilms. Strategies to tackle antibiotic resistance as well as biofilms are urgently needed. Wall teichoic acid (WTA), a generic anionic glycopolymer present on the cell surface of many Gram-positive bacteria, has been proposed as a possible therapeutic target, but its druggability remains to be demonstrated. Here we report a cationic glycosylated block co-β-peptide that binds to WTA. By doing so, the co-β-peptide not only inhibits biofilm formation, it also disperses preformed biofilms in several Gram-positive bacteria and resensitizes methicillin-resistant Staphylococcus aureus to oxacillin. The cationic block of the co-β-peptide physically interacts with the anionic WTA within the cell envelope, whereas the glycosylated block forms a nonfouling corona around the bacteria. This reduces physical interaction between bacteria-substrate and bacteria-biofilm matrix, leading to biofilm inhibition and dispersal. The WTA-targeting co-β-peptide is a promising lead for the future development of broad-spectrum anti-biofilm strategies against Gram-positive bacteria.
  • Journal article
    Lossi NS, Manoli E, Foerster A, Dajani R, Pape T, Freemont P, Filloux Aet al., 2021,

    The HsiB1C1 (TssB-TssC) complex of the pseudomonas aeruginosa Type VI secretion system forms a bacteriophage tail sheathlike structure

    , Journal of Biological Chemistry, Vol: 288, Pages: 7536-7548, ISSN: 0021-9258

    Protein secretion systems in Gram-negative bacteria evolved into a variety of molecular nanomachines. They are related to cell envelope complexes, which are involved in assembly of surface appendages or transport of solutes. They are classified as types, the most recent addition being the type VI secretion system (T6SS). The T6SS displays similarities to bacteriophage tail, which drives DNA injection into bacteria. The Hcp protein is related to the T4 bacteriophage tail tube protein gp19, whereas VgrG proteins structurally resemble the gp27/gp5 puncturing device of the phage. The tube and spike of the phage are pushed through the bacterial envelope upon contraction of a tail sheath composed of gp18. In Vibrio cholerae it was proposed that VipA and VipB assemble into a tail sheathlike structure. Here we confirm these previous data by showing that HsiB1 and HsiC1 of the Pseudomonas aeruginosa H1-T6SS assemble into tubules resulting from stacking of cogwheel-like structures showing predominantly 12-fold symmetry. The internal diameter of the cogwheels is ∼100 Å, which is large enough to accommodate an Hcp tube whose external diameter has been reported to be 85 Å. The N-terminal 212 residues of HsiC1 are sufficient to form a stable complex with HsiB1, but the C terminus of HsiC1 is essential for the formation of the tubelike structure. Bioinformatics analysis suggests that HsiC1 displays similarities to gp18-like proteins in its C-terminal region. In conclusion, we provide further structural and mechanistic insights into the T6SS and show that a phage sheathlike structure is likely to be a conserved element across all T6SSs.
  • Journal article
    Pathania M, Tosi T, Millership C, Hoshiga F, Morgan R, Freemont P, Gründling Aet al., 2021,

    Structural basis for the inhibition of the <i>Bacillus subtilis</i> c-di-AMP cyclase CdaA by the phosphoglucomutase GlmM

    Cyclic-di-adenosine monophosphate (c-di-AMP) is an important nucleotide signalling molecule, which plays a key role in osmotic regulation in bacteria. Cellular c-di-AMP levels are tightly regulated, as both high and low levels have a negative impact on bacterial growth. Here, we investigated how the activity of the main Bacillus subtilis c-di-AMP cyclase CdaA is regulated by the phosphoglucomutase GlmM. c-di-AMP is produced from two molecules of ATP by proteins containing a deadenylate cyclase (DAC) domain. CdaA is a membrane-linked cyclase with an N-terminal transmembrane domain followed by the cytoplasmic DAC domain. Here we show, using the soluble catalytic B. subtilis CdaA CD domain and purified full-length GlmM or the GlmM F369 variant lacking the C-terminal flexible domain 4, that the cyclase and phosphoglucomutase form a stable complex in vitro and that GlmM is a potent cyclase inhibitor. We determined the crystal structure of the individual B. subtilis CdaA CD and GlmM proteins, both of which form dimers in the structures, and of the CdaA CD GlmM F369 complex. In the complex structure, a CdaA CD dimer is bound to a GlmM F369 dimer in such a manner that GlmM blocks the oligomerization of CdaA CD and formation of active head-to-head cyclase oligomers, thus providing molecular details on how GlmM acts as cyclase inhibitor. The function of a key amino acid residue in CdaA CD in complex formation was confirmed by mutagenesis analysis. As the amino acids at the CdaA CD GlmM interphase are conserved, we propose that the observed inhibition mechanism of CdaA by GlmM is conserved among Firmicutes.
  • Journal article
    Michaux C, Ronneau S, Helaine S, 2021,

    Studying Antibiotic Persistence During Infection

    , BACTERIAL PERSISTENCE, 2 EDITION, Pages: 273-289, ISSN: 1064-3745
  • Journal article
    McCarthy RR, Larrouy-Maumus GJ, Tan MGCM, Wareham DWet al., 2021,

    Antibiotic Resistance Mechanisms and Their Transmission in <i>Acinetobacter baumannii</i>

    , MICROBIAL PATHOGENESIS: INFECTION AND IMMUNITY, 2ND EDITION, Vol: 1313, Pages: 135-153, ISSN: 0065-2598
  • Journal article
    Hopkins EGD, Frankel G, 2021,

    Overview of the Effect of <i>Citrobacter rodentium</i> Infection on Host Metabolism and the Microbiota

    , SHIGA TOXIN-PRODUCING E. COLI, Vol: 2291, Pages: 399-418, ISSN: 1064-3745

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