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Journal articleZheng W, Peña A, Ilangovan A, et 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: 0027-8424Enteropathogenic 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.
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Journal articleZhang K, Raju C, Zhong W, et 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: 2576-6422Antimicrobial 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.
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Journal articleLossi NS, Manoli E, Foerster A, et 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: 0021-9258Protein 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.
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Journal articleHopkins 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- Author Web Link
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- Citations: 4
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Journal articlePathania M, Tosi T, Millership C, et 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.
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Journal articleMcCarthy RR, Larrouy-Maumus GJ, Tan MGCM, et 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- Author Web Link
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- Citations: 4
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Journal articleMichaux C, Ronneau S, Helaine S, 2021,
Studying Antibiotic Persistence During Infection
, BACTERIAL PERSISTENCE, 2 EDITION, Pages: 273-289, ISSN: 1064-3745- Author Web Link
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- Citations: 4
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Journal articlePotter M, Najer A, Kloeckner A, et al., 2020,
Controlled dendrimersome nanoreactor system for localised hypochlorite-induced killing of bacteria
, ACS Nano, Vol: 14, Pages: 17333-17353, ISSN: 1936-0851Antibiotic resistance is a serious global health problem necessitating new bactericidal approaches such as nanomedicines. Dendrimersomes (DSs) have recently become a valuable alternative nanocarrier to polymersomes and liposomes due to their molecular definition and synthetic versatility. Despite this, their biomedical application is still in its infancy. Inspired by the localized antimicrobial function of neutrophil phagosomes and the versatility of DSs, a simple three-component DS-based nanoreactor with broad-spectrum bactericidal activity is presented. This was achieved by encapsulation of glucose oxidase (GOX) and myeloperoxidase (MPO) within DSs (GOX-MPO-DSs), self-assembled from an amphiphilic Janus dendrimer, that possesses a semipermeable membrane. By external addition of glucose to GOX-MPO-DS, the production of hypochlorite (−OCl), a highly potent antimicrobial, by the enzymatic cascade was demonstrated. This cascade nanoreactor yielded a potent bactericidal effect against two important multidrug resistant pathogens, Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa), not observed for H2O2 producing nanoreactors, GOX-DS. The production of highly reactive species such as –OCl represents a harsh bactericidal approach that could also be cytotoxic to mammalian cells. This necessitates the development of strategies for activating –OCl production in a localized manner in response to a bacterial stimulus. One option of locally releasing sufficient amounts of substrate using a bacterial trigger (released toxins) was demonstrated with lipidic glucose-loaded giant unilamellar vesicles (GUVs), envisioning, e.g., implant surface modification with nanoreactors and GUVs for localized production of bactericidal agents in the presence of bacterial growth.
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Journal articleMullish BH, Michael DR, McDonald JAK, et al., 2020,
Identifying the factors influencing outcome in probiotic studies in overweight and obese patients – host or microbiome?
, Gut, Vol: 70, Pages: 225-226, ISSN: 0017-5749 -
Journal articleLiu Z, Coales I, Penney N, et al., 2020,
A Subset of Roux-en-Y Gastric Bypass Bacterial Consortium Colonizes the Gut of Nonsurgical Rats without Inducing Host-Microbe Metabolic Changes.
, mSystems, Vol: 5, ISSN: 2379-5077Roux-en-Y gastric bypass (RYGB) is an effective weight loss surgery, resulting in a characteristic increase of fecal Gammaproteobacteria The contribution of this compositional change to metabolic benefits of RYGB is currently debatable. Therefore, this study employed 16S rRNA gene sequencing and metabolic profiling to monitor the dynamic colonization of the RYGB microbial consortium and their metabolic impact on the host. Eleven Wistar rats received vancomycin and enrofloxacin, followed by fecal microbiota transplantation (FMT) of cecal slurry obtained from either RYGB- or sham-operated rats. Urine and feces from the microbiota recipients (RYGB microbiota recipients [RYGBr], n = 6; sham microbiota recipients [SHAMr], n = 5) were collected pre- and post-antibiotics and 1, 3, 6, 9, and 16 days post-FMT. No significant differences in body weight and food intake were observed between RYGBr and SHAMr. While neither group reached the community richness of that of their donors, by day 6, both groups reached the richness and diversity of that prior to antibiotic treatment. However, the typical signature of RYGB microbiome-increased Enterobacteriaceae-was not replicated in these recipients after two consecutive FMT, suggesting that the environmental changes induced by the anatomical rearrangements of RYGB could be key for sustaining such a consortium. The transplanted bacteria did not induce the same metabolic signature of urine and feces as those previously reported in RYGB-operated rats. Future work is required to explore environmental factors that shape the RYGB microbiota in order to further investigate the metabolic functions of the RYGB microbiota, thereby teasing out the mechanisms of the RYGB surgery.IMPORTANCE Roux-en-Y gastric bypass (RYGB) surgery results in a long-term gut bacterial shift toward Gammaproteobacteria in both patients and rodents. The contribution of this compositional shift, or the RYGB bacterial consortium, to th
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