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  • Journal article
    Nolan AC, Zeden MS, Campbell C, Kviatkovski I, Urwin L, Corrigan RM, Gründling A, OGara JPet al., 2022,

    Purine nucleosides interfere with c-di-AMP levels and act as adjuvants to re-sensitise MRSA to β-lactam antibiotics

    <jats:title>Abstract</jats:title><jats:p>Elucidating the complex mechanisms controlling <jats:italic>mecA</jats:italic>/PBP2a-mediated β-lactam resistance in methicillin resistant <jats:italic>Staphylococcus aureus</jats:italic> (MRSA) has the potential to identify new drug targets with therapeutic potential. Here, we report that mutations that interfere with <jats:italic>de novo</jats:italic> purine synthesis (<jats:italic>pur</jats:italic> operon), purine transport (NupG, PbuG and PbuX) and the nucleotide salvage pathway (DeoD2, Hpt) increased β-lactam resistance in MRSA strain JE2. Extrapolating from these findings, exogenous guanosine and xanthosine, which are fluxed through the GTP branch of purine biosynthesis were shown to significantly reduce MRSA β-lactam resistance. In contrast adenosine, which is fluxed to ATP, significantly increased oxacillin resistance, whereas inosine, which can be fluxed to ATP and GTP via hypoxanthine, only marginally reduced the oxacillin MIC. Increased oxacillin resistance of the <jats:italic>nupG</jats:italic> mutant was not significantly reversed by guanosine, indicating that NupG is required for guanosine transport, which in turn is required to reduce β-lactam resistance. Suppressor mutants resistant to oxacillin/guanosine combinations contained several purine salvage pathway mutations, including <jats:italic>nupG</jats:italic> and <jats:italic>hpt</jats:italic>. Microscopic analysis revealed that guanosine significantly increased cell size, a phenotype also associated with reduced levels of c-di-AMP. Consistent with this, guanosine significantly reduced levels of c-di-AMP, and inactivation of GdpP, the c-di-AMP phosphodiesterase negated the impact of guanosine on β-lactam susceptibility. PBP2a expression was unaffected in <jats:italic>nupG</jats:italic> or <jats:italic>deoD2</jats:

  • Journal article
    Vincent CS, Beckwith E, Simoes da Silva C, Pearson W, Kierdorf K, Gilestro G, Dionne Met al., 2022,

    Infection increases activity via Toll dependent and independent mechanisms in <i>Drosophila melanogaster</i>

    , PLOS PATHOGENS, Vol: 18, ISSN: 1553-7366
  • Journal article
    Boeck L, Burbaud S, Skwark M, Pearson WH, Sangen J, Wuest AW, Marshall EKP, Weimann A, Everall I, Bryant JM, Malhotra S, Bannerman BP, Kierdorf K, Blundell TL, Dionne MS, Parkhill J, Floto RAet al., 2022,

    <i>Mycobacterium abscessus</i> pathogenesis identified by phenogenomic analyses

    , NATURE MICROBIOLOGY, Vol: 7, Pages: 1431-+, ISSN: 2058-5276
  • Journal article
    Hamilton C, Olona A, Leishman S, MacDonald-Ramsahai K, Cockcroft S, Larrouy-Maumus G, Anand Pet al., 2022,

    NLRP3 inflammasome priming and activation are regulated by a phosphatidylinositol-dependent mechanism

    , ImmunoHorizons, Vol: 6, ISSN: 2573-7732

    Imbalance in lipid homeostasis is associated with discrepancies in immune signaling and is tightly linked to metabolic disorders. The diverse ways in which lipids impact immune signaling, however, remain ambiguous. The phospholipid phosphatidylinositol (PI), which is implicated in numerous immune disorders, is chiefly defined by its phosphorylation status. By contrast, the significance of the two fatty acid chains attached to the PI remains unknown. Here, by employing a mass-spectrometry-based assay, we demonstrate a role for PI acyl group chains in regulating both the priming and activation steps of the NLRP3 inflammasome in mouse macrophages. In response to NLRP3 stimuli, cells deficient in ABC transporter ABCB1, which effluxes lipid derivatives, revealed defective inflammasome activation. Mechanistically, Abcb1-deficiency shifted the total PI configuration exhibiting a reduced ratio of short-chain to long-chain PI acyl lipids. Consequently, Abcb1-deficiency initiated the rapid degradation of TIRAP, the TLR adaptor protein which binds PI (4,5)-bisphosphate, resulting in defective TLR-dependent signaling, and thus NLRP3 expression. Moreover, this accompanied increased NLRP3 phosphorylation at the Ser291 position and contributed to blunted inflammasome activation. Exogenously supplementing WT cells with linoleic acid, but not arachidonic acid, reconfigured PI acyl chains. Accordingly, linoleic acid supplementation increased TIRAP degradation, elevated NLRP3 phosphorylation, and abrogated inflammasome activation. Furthermore, NLRP3 Ser291 phosphorylation was dependent on prostaglandin E2-induced protein kinase A signaling as pharmacological inhibition of this pathway in linoleic acid-enriched cells dephosphorylated NLRP3. Altogether, our study reveals a novel metabolic-inflammatory circuit which contributes to calibrating immune responses.

  • Journal article
    Wang G, Brunel J-M, Preusse M, Mozaheb N, Willger SD, Larrouy-Maumus G, Baatsen P, Haeussler S, Bolla J-M, Van Bambeke Fet al., 2022,

    The membrane-active polyaminoisoprenyl compound NV716 re-sensitizes <i>Pseudomonas aeruginosa</i> to antibiotics and reduces bacterial virulence

  • Journal article
    Pizzato J, Tang W, Bernabeu S, Bonnin RA, Bille E, Farfour E, Guillard T, Barraud O, Cattoir V, Plouzeau C, Corvec S, Shahrezaei V, Dortet L, Larrouy-Maumus Get al., 2022,

    Discrimination of Escherichia coli, Shigella flexneri, and Shigella sonnei using lipid profiling by MALDI-TOF mass spectrometry paired with machine learning

    , MicrobiologyOpen, Vol: 11, Pages: 1-14, ISSN: 2045-8827

    Matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) has become a staple in clinical microbiology laboratories. Protein-profiling of bacteria using this technique has accelerated the identification of pathogens in diagnostic workflows. Recently, lipid profiling has emerged as a way to complement bacterial identification where protein-based methods fail to provide accurate results. This study aimed to address the challenge of rapid discrimination between Escherichia coli and Shigella spp. using MALDI-TOF MS in the negative ion mode for lipid profiling coupled with machine learning. Both E. coli and Shigella species are closely related; they share high sequence homology, reported for 16S rRNA gene sequence similarities between E. coli and Shigella spp. exceeding 99%, and a similar protein expression pattern but are epidemiologically distinct. A bacterial collection of 45 E. coli, 48 Shigella flexneri, and 62 Shigella sonnei clinical isolates were submitted to lipid profiling in negative ion mode using the MALDI Biotyper Sirius® system after treatment with mild-acid hydrolysis (acetic acid 1% v/v for 15 min at 98°C). Spectra were then analyzed using our in-house machine learning algorithm and top-ranked features used for the discrimination of the bacterial species. Here, as a proof-of-concept, we showed that lipid profiling might have the potential to differentiate E. coli from Shigella species using the analysis of the top five ranked features obtained by MALDI-TOF MS in the negative ion mode of the MALDI Biotyper Sirius® system. Based on this new approach, MALDI-TOF MS analysis of lipids might help pave the way toward these goals.

  • Journal article
    Fillol-Salom A, Rostøl JT, Ojiogu AD, Chen J, Douce G, Humphrey S, Penadés JRet al., 2022,

    Bacteriophages benefit from mobilizing pathogenicity islands encoding immune systems against competitors

    , Cell, Vol: 185, Pages: 3248-3262.e20, ISSN: 0092-8674

    Bacteria encode sophisticated anti-phage systems that are diverse and versatile and display high genetic mobility. How this variability and mobility occurs remains largely unknown. Here, we demonstrate that a widespread family of pathogenicity islands, the phage-inducible chromosomal islands (PICIs), carry an impressive arsenal of defense mechanisms, which can be disseminated intra- and inter-generically by helper phages. These defense systems provide broad immunity, blocking not only phage reproduction, but also plasmid and non-cognate PICI transfer. Our results demonstrate that phages can mobilize PICI-encoded immunity systems to use them against other mobile genetic elements, which compete with the phages for the same bacterial hosts. Therefore, despite the cost, mobilization of PICIs may be beneficial for phages, PICIs, and bacteria in nature. Our results suggest that PICIs are important players controlling horizontal gene transfer and that PICIs and phages establish mutualistic interactions that drive bacterial ecology and evolution.

  • Journal article
    Farne H, Lin L, Jackson D, Rattray M, Simpson A, Custovic A, Joshi S, Wilson P, Williamson R, Edwards M, Singanayagam A, Johnston Set al., 2022,

    In vivo bronchial epithelial interferon responses are augmented in asthma on day 4 following experimental rhinovirus infection

    , Thorax, Vol: 77, Pages: 929-932, ISSN: 0040-6376

    Despite good evidence of impaired innate antiviral responses in asthma, trials of inhaled interferon-β given during exacerbations showed only modest benefits in moderate/severe asthma. Using human experimental rhinovirus infection, we observe robust in vivo induction of bronchial epithelial interferon response genes four days after virus inoculation in 25 subjects with asthma but not 11 control subjects. This signature correlated with virus loads and lower respiratory symptoms. Our data indicate that the in vivo innate antiviral response is dysregulated in asthma and open up the potential that prophylactic rather than therapeutic interferon therapy may have greater clinical benefit.

  • Journal article
    Wadhawan A, Simoes da Silva CJ, Nunes CD, Edwards AM, Dionne MSet al., 2022,

    <i>E. faecalis</i>acquires resistance to antimicrobials and insect immunity via common mechanisms

    <jats:title>Summary</jats:title><jats:p><jats:italic>Enterococcus faecalis</jats:italic>is a normal member of the gut microbiota and an opportunistic pathogen of many animals, including mammals, birds, and insects. It is a common cause of nosocomial infections, and is particularly troublesome due to extensive intrinsic and acquired antimicrobial resistance. Using experimental evolution, we generated<jats:italic>Drosophila</jats:italic>-adapted<jats:italic>E. faecalis</jats:italic>strains, which exhibited immune resistance, resulting in increased<jats:italic>in vivo</jats:italic>growth and virulence. Resistance was characterised by mutations in bacterial pathways responsive to cell envelope stress.<jats:italic>Drosophila</jats:italic>-adapted strains exhibited changes in sensitivity to relevant antimicrobials, including daptomycin and vancomycin. Evolved daptomycin-resistant strains harboured mutations in the same signalling systems, with some strains showing increased virulence similar to<jats:italic>Drosophila</jats:italic>-adapted strains. Our results show that common mechanisms provide a route to resistance to both antimicrobials and host immunity in<jats:italic>E. faecalis</jats:italic>and demonstrate that the selection and emergence of antibiotic resistance<jats:italic>in vivo</jats:italic>does not require antibiotic exposure.</jats:p><jats:sec><jats:title>One sentence summary</jats:title><jats:p>Host interaction can promote antimicrobial resistance and antimicrobial treatment can promote virulence in<jats:italic>E. faecalis</jats:italic>.</jats:p></jats:sec>

  • Journal article
    Ledger EVK, Edwards AM, 2022,

    Growth arrest of<i>Staphylococcus aureus</i>induces daptomycin tolerance via cell wall remodelling

    <jats:title>Abstract</jats:title><jats:p>Almost all bactericidal drugs require bacterial replication and/or metabolic activity for their killing activity. When these processes are inhibited by bacteriostatic antibiotics, bacterial killing is significantly reduced. One notable exception is the lipopeptide antibiotic daptomycin, which has been reported to efficiently kill non-dividing bacteria. However, these studies employed only brief periods of growth arrest. We found that a bacteriostatic concentration of the protein synthesis inhibitor tetracycline led to a time-dependent induction of daptomycin tolerance in<jats:italic>S. aureus</jats:italic>, with<jats:sup>~</jats:sup>100,000-fold increase in survival after 16 h growth arrest relative to exponential phase bacteria. Daptomycin tolerance required glucose and was associated with increased production of the cell wall polymers peptidoglycan and wall-teichoic acids. However, whilst accumulation of peptidoglycan was required for daptomycin tolerance, only a low abundance of wall teichoic acid was necessary. Therefore, whilst tolerance to most antibiotics occurs passively due to a lack of metabolic activity and/or replication, daptomycin tolerance arises via active cell wall remodelling.</jats:p>

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