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  • Journal article
    Humphrey S, Fillol-Salom A, Quiles-Puchalt N, Ibarra-Chávez R, Haag A, Chen J, Penades Jet al., 2021,

    Bacterial chromosomal mobility via lateral transduction exceeds that of classical mobile genetic elements

    , Nature Communications, Vol: 12, Pages: 1-12, ISSN: 2041-1723

    It is commonly assumed that the horizontal transfer of most bacterial chromosomal genes is limited, in contrast to the frequent transfer observed for typical mobile genetic elements. However, this view has been recently challenged by the discovery of lateral transduction in Staphylococcus aureus, where temperate phages can drive the transfer of large chromosomalregions at extremely high frequencies. Here, we analyse previously published as well as new datasets to compare horizontal gene transfer rates mediated by different mechanisms in S. aureus and Salmonella enterica. We find that the horizontal transfer of core chromosomal genes via lateral transduction can be more efficient than the transfer of classical mobile genetic elements via conjugation or generalized transduction. These results raise questions about our definition of mobile genetic elements, and the potential roles played by lateral transduction in bacterial evolution.

  • Journal article
    Liu B, Li S, Liu Y, Chen H, Hu Z, Wang Z, Zhao Y, Zhang L, Ma B, Wang H, Matthews S, Wang Y, Zhang Ket al., 2021,

    Bacteriophage Twort protein Gp168 is a β-clamp inhibitor by occupying the DNA sliding channel

    , NUCLEIC ACIDS RESEARCH, Vol: 49, Pages: 11367-11378, ISSN: 0305-1048
  • Journal article
    Hawkins NC, Kizziah JL, Penades JR, Dokland Tet al., 2021,

    Shape shifter: redirection of prolate phage capsid assembly by staphylococcal pathogenicity islands

    , NATURE COMMUNICATIONS, Vol: 12
  • Journal article
    Humphrey M, Larrouy-Maumus GJ, Furniss RCD, Mavridou DA, Sabnis A, Edwards AMet al., 2021,

    Colistin resistance in Escherichia coli confers protection of the cytoplasmic but not outer membrane from the polymyxin antibiotic

    , MICROBIOLOGY-SGM, Vol: 167, Pages: 1-9, ISSN: 1350-0872

    Colistin is a polymyxin antibiotic of last resort for the treatment of infections caused by multi-drug-resistant Gram-negative bacteria. By targeting lipopolysaccharide (LPS), the antibiotic disrupts both the outer and cytoplasmic membranes, leading to bacterial death and lysis. Colistin resistance in Escherichia coli occurs via mutations in the chromosome or the acquisition of mobilized colistin-resistance (mcr) genes. Both these colistin-resistance mechanisms result in chemical modifications to the LPS, with positively charged moieties added at the cytoplasmic membrane before the LPS is transported to the outer membrane. We have previously shown that MCR-1-mediated LPS modification protects the cytoplasmic but not the outer membrane from damage caused by colistin, enabling bacterial survival. However, it remains unclear whether this observation extends to colistin resistance conferred by other mcr genes, or resistance due to chromosomal mutations. Using a panel of clinical E. coli that had acquired mcr −1, –1.5, −2, –3, −3.2 or −5, or had acquired polymyxin resistance independently of mcr genes, we found that almost all isolates were susceptible to colistin-mediated permeabilization of the outer, but not cytoplasmic, membrane. Furthermore, we showed that permeabilization of the outer membrane of colistin-resistant isolates by the polymyxin is in turn sufficient to sensitize bacteria to the antibiotic rifampicin, which normally cannot cross the LPS monolayer. These findings demonstrate that colistin resistance in these E. coli isolates is due to protection of the cytoplasmic but not outer membrane from colistin-mediated damage, regardless of the mechanism of resistance.

  • Journal article
    Wan Y, Myall AC, Boonyasiri A, Bolt F, Ledda A, Mookerjee S, Weiße AY, Getino M, Turton JF, Abbas H, Prakapaite R, Sabnis A, Abdolrasoulia A, Malpartida-Cardenas K, Miglietta L, Donaldson H, Gilchrist M, Hopkins KL, Ellington MJ, Otter JA, Larrouy-Maumus G, Edwards AM, Rodriguez-Manzano J, Didelot X, Barahona M, Holmes AH, Jauneikaite E, Davies Fet al., 2021,

    Integrated analysis of patient networks and plasmid genomes reveals a regional, multi-species outbreak of carbapenemase-producing Enterobacterales carrying both<i>bla</i><sub>IMP</sub>and<i>mcr-9</i>genes

    <jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Carbapenemase-producing Enterobacterales (CPE) are challenging in the healthcare setting, with resistance to multiple classes of antibiotics and a high associated mortality. The incidence of CPE is rising globally, despite enhanced awareness and control efforts. This study describes an investigation of the emergence of IMP-encoding CPE amongst diverse Enterobacterales species between 2016 and 2019 in patients across a London regional hospital network.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We carried out a network analysis of patient pathways, using electronic health records, to identify contacts between IMP-encoding CPE positive patients. Genomes of IMP-encoding CPE isolates were analysed and overlayed with patient contacts to imply potential transmission events.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Genomic analysis of 84 Enterobacterales isolates revealed diverse species (predominantly<jats:italic>Klebsiella</jats:italic>spp,<jats:italic>Enterobacter</jats:italic>spp,<jats:italic>E. coli</jats:italic>), of which 86% (72/84) harboured an IncHI2 plasmid, which carried both<jats:italic>bla</jats:italic><jats:sub>IMP</jats:sub>and the mobile colistin resistance gene<jats:italic>mcr-9</jats:italic>(68/72). Phylogenetic analysis of IncHI2 plasmids identified three lineages which showed significant association with patient contact and movements between four hospital sites and across medical specialities, which had been missed on initial investigations.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Combined, our patient network and plasmid analyses demonstrate an interspecies, plasmid-med

  • Journal article
    Pathania M, Tosi T, Millership C, Hoshiga F, Morgan RML, Freemont PS, Grundling Aet al., 2021,

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

    , Journal of Biological Chemistry, Vol: 297, Pages: 1-15, ISSN: 0021-9258

    Cyclic-di-adenosine monophosphate (c-di-AMP) is an important nucleotide signaling molecule that plays a key role in osmotic regulation in bacteria. c-di-AMP is produced from two molecules of ATP by proteins containing a diadenylate cyclase (DAC) domain. In Bacillus subtilis, the main c-di-AMP cyclase, CdaA, is a membrane-linked cyclase with an N-terminal transmembrane domain followed by the cytoplasmic DAC domain. As both high and low levels of c-di-AMP have a negative impact on bacterial growth, the cellular levels of this signaling nucleotide are tightly regulated. Here we investigated how the activity of the B. subtilis CdaA is regulated by the phosphoglucomutase GlmM, which has been shown to interact with the c-di-AMP cyclase. Using the soluble B. subtilis CdaACD catalytic domain and purified full-length GlmM or the GlmMF369 variant lacking the C-terminal flexible domain 4, we show 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 CdaACD and GlmM homodimers and of the CdaACD:GlmMF369 complex. In the complex structure, a CdaACD dimer is bound to a GlmMF369 dimer in such a manner that GlmM blocks the oligomerization of CdaACD and formation of active head-to-head cyclase oligomers, thus suggesting a mechanism by which GlmM acts as a cyclase inhibitor. As the amino acids at the CdaACD:GlmM interphase are conserved, we propose that the observed mechanism of inhibition of CdaA by GlmM may also be conserved among Firmicutes.

  • Journal article
    McKenna S, Giblin SP, Bunn RA, Xu Y, Matthews SJ, Pease JEet al., 2021,

    A highly efficient method for the production and purification of recombinant human CXCL8

    , PLoS One, Vol: 16, Pages: 1-12, ISSN: 1932-6203

    Chemokines play diverse and fundamental roles in the immune system and human disease, which has prompted their structural and functional characterisation. Production of recombinant chemokines that are folded and bioactive is vital to their study but is limited by the stringent requirements of a native N-terminus for receptor activation and correct disulphide bonding required to stabilise the chemokine fold. Even when expressed as fusion proteins, overexpression of chemokines in E. coli tends to result in the formation of inclusion bodies, generating the additional steps of solubilisation and refolding. Here we present a novel method for producing soluble chemokines in relatively large amounts via a simple two-step purification procedure with no requirements for refolding. CXCL8 produced by this method has the correct chemokine fold as determined by NMR spectroscopy and in chemotaxis assays was indistinguishable from commercially available chemokines. We believe that this protocol significantly streamlines the generation of recombinant chemokines.

  • Journal article
    Pruski P, Dos Santos Correia G, Lewis H, Capuccini K, Inglese P, Chan D, Brown R, Kindinger L, Lee Y, Smith A, Marchesi J, McDonald J, Cameron S, Alexander-Hardiman K, David A, Stock S, Norman J, Terzidou V, Teoh TG, Sykes L, Bennett P, Takats Z, MacIntyre Det al., 2021,

    Direct on-swab metabolic profiling of vaginal microbiome host interactions during pregnancy and preterm birth

    , Nature Communications, Vol: 12, ISSN: 2041-1723

    The pregnancy vaginal microbiome contributes to risk of preterm birth, the primary cause of death in children under 5 years of age. Here we describe direct on-swab metabolic profiling by Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) for sample preparation-free characterisation of the cervicovaginal metabolome in two independent pregnancy cohorts (VMET, n = 160; 455 swabs; VMET II, n = 205; 573 swabs). By integrating metataxonomics and immune profiling data from matched samples, we show that specific metabolome signatures can be used to robustly predict simultaneously both the composition of the vaginal microbiome and host inflammatory status. In these patients, vaginal microbiota instability and innate immune activation, as predicted using DESI-MS, associated with preterm birth, including in women receiving cervical cerclage for preterm birth prevention. These findings highlight direct on-swab metabolic profiling by DESI-MS as an innovative approach for preterm birth risk stratification through rapid assessment of vaginal microbiota-host dynamics.

  • Journal article
    Humphrey S, San Millan A, Toll-Riera M, Connolly J, Flor-Duro A, Chen J, Ubeda C, MacLean RC, Penades Jet al., 2021,

    Staphylococcal phages and pathogenicity islands drive plasmid evolution

    , Nature Communications, Vol: 12, Pages: 1-15, ISSN: 2041-1723

    Conjugation has classically been considered the main mechanism driving plasmid transfer in nature. Yet bacteria frequently carry so-called non-transmissible plasmids, raising questions about how these plasmids spread. Interestingly, the size of many mobilizable and non transmissible plasmids coincides with the average size of phages (~40kb) or that of a family of pathogenicity islands, the phage-inducible chromosomal islands (PICIs, ~11 kb). Here, we show that phages and PICIs from Staphylococcus aureus can mediate intra- and inter-species plasmid transfer via generalised transduction, potentially contributing to non-transmissible plasmid spread in nature. Further, staphylococcal PICIs enhance plasmid packaging efficiency, and phages and PICIs exert selective pressures on plasmids via the physical capacity of their capsids, explaining the bimodal size distribution observed for non-conjugative plasmids. Our results highlight that transducing agents (phages, PICIs) have important roles in bacterial plasmid evolution and, potentially, in antimicrobial resistance transmission.

  • Journal article
    Mullineaux Sanders C, Carson D, Hopkins E, Glegola-Madejska I, Escobar-Zepeda A, Browne H, Lawley T, Frankel Get al., 2021,

    Citrobacter amalonaticus inhibits the growth of Citrobacter rodentium in the gut lumen

    , mBio, Vol: 5, Pages: 1-19, ISSN: 2150-7511

    The gut microbiota plays a crucial role in susceptibility to enteric pathogens, including Citrobacter rodentium, a model extracellular mouse pathogen that colonizes the colonic mucosa. C. rodentium infection outcomes vary between mouse strains, with C57BL/6 and C3H/HeN mice clearing or succumbing to the infection respectively. Kanamycin (Kan) treatment at the peak of C57BL/6 mouse infection with Kan-resistant C. rodentium resulted in re-localisation of the pathogen from the colonic mucosa and cecum to solely the cecal luminal contents; cessation of the Kan treatment resulted in rapid clearance of the pathogen. We now show that in C3H/HeN mice, following Kan-induced displacement of C. rodentium to the cecum, the pathogen stably colonizes the cecal lumen of 65% of the mice in the absence of continued antibiotic treatment, a phenomenon we term antibiotic-induced bacterial commensalisation (AIBC). AIBC C. rodentium was well-tolerated by the host, which showed little signs of inflammation; passaged AIBC C. rodentium robustly infected naïve C3H/HeN mice suggesting that the AIBC state is transient and did not select for genetically avirulent C. rodentium mutants. Following withdrawal of antibiotic treatment, 35% of C3H/HeN mice were able to prevent C. rodentium commensalisation in the gut lumen. These mice presented a bloom of a commensal species, Citrobacter amalonaticus, which inhibited the growth of C. rodentium in vitro in a contact-dependant manner, and luminal growth of AIBC C. rodentium in vivo. Overall our data suggest that commensal species can confer colonization resistance against closely-related pathogenic species.

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