{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T17:17:42Z","timestamp":1761844662213},"reference-count":58,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,11,3]],"date-time":"2016-11-03T00:00:00Z","timestamp":1478131200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,11,3]],"date-time":"2016-11-03T00:00:00Z","timestamp":1478131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>Streptococcus pyogenes<\/jats:italic> is a globally prominent bacterial pathogen that exhibits strict tropism for the human host, yet bacterial factors responsible for the ability of <jats:italic>S. pyogenes<\/jats:italic> to compete within this limited biological niche are not well understood. Using an engineered recombinase-based <jats:italic>in vivo<\/jats:italic> expression technology (RIVET) system, we identified an <jats:italic>in vivo<\/jats:italic>-induced promoter region upstream of a predicted Class IIb bacteriocin system in the M18 serotype <jats:italic>S. pyogenes<\/jats:italic> strain MGAS8232. This promoter element was not active under <jats:italic>in vitro<\/jats:italic> laboratory conditions, but was highly induced within the mouse nasopharynx. Recombinant expression of the predicted mature <jats:italic>S. pyogenes<\/jats:italic> bacteriocin peptides (designated SpbM and SpbN) revealed that both peptides were required for antimicrobial activity. Using a gain of function experiment in <jats:italic>Lactococcus lactis<\/jats:italic>, we further demonstrated <jats:italic>S. pyogenes<\/jats:italic> immunity function is encoded downstream of <jats:italic>spbN<\/jats:italic>. These data highlight the importance of bacterial gene regulation within appropriate environments to help understand mechanisms of niche adaptation by bacterial pathogens.<\/jats:p>","DOI":"10.1038\/srep36233","type":"journal-article","created":{"date-parts":[[2016,11,3]],"date-time":"2016-11-03T10:21:35Z","timestamp":1478168495000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Identification of a two-component Class IIb bacteriocin in Streptococcus pyogenes by recombinase-based in vivo expression technology"],"prefix":"10.1038","volume":"6","author":[{"given":"Brent D.","family":"Armstrong","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine A.","family":"Herfst","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas C.","family":"Tonial","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrienne T.","family":"Wakabayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph J.","family":"Zeppa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John K.","family":"McCormick","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,11,3]]},"reference":[{"key":"BFsrep36233_CR1","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1128\/CMR.00101-13","volume":"27","author":"MJ Walker","year":"2014","unstructured":"Walker, M. J. et al. Disease manifestations and pathogenic mechanisms of group A Streptococcus. Clin Microbiol Rev 27, 264\u2013301 (2014).","journal-title":"Clin Microbiol Rev"},{"key":"BFsrep36233_CR2","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/S1473-3099(05)70267-X","volume":"5","author":"JR Carapetis","year":"2005","unstructured":"Carapetis, J. R., Steer, A. C., Mulholland, E. K. & Weber, M. The global burden of group A streptococcal diseases. Lancet Infect Dis 5, 685\u2013694 (2005).","journal-title":"Lancet Infect Dis"},{"key":"BFsrep36233_CR3","first-page":"1","volume":"368","author":"AP Ralph","year":"2013","unstructured":"Ralph, A. P. & Carapetis, J. R. Group A streptococcal diseases and their global burden. Curr Top Microbiol Immunol 368, 1\u201327 (2013).","journal-title":"Curr Top Microbiol Immunol"},{"key":"BFsrep36233_CR4","doi-asserted-by":"publisher","first-page":"623","DOI":"10.2217\/fmb.10.28","volume":"5","author":"DE Bessen","year":"2010","unstructured":"Bessen, D. E. & Lizano, S. Tissue tropisms in group A streptococcal infections. Future Microbiol 5, 623\u2013638 (2010).","journal-title":"Future Microbiol"},{"key":"BFsrep36233_CR5","doi-asserted-by":"crossref","unstructured":"Reglinski, M. & Sriskandan, S. The contribution of group A streptococcal virulence determinants to the pathogenesis of sepsis. Virulence 5 (2013).","DOI":"10.4161\/viru.26400"},{"key":"BFsrep36233_CR6","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.tim.2007.05.001","volume":"15","author":"AH Tart","year":"2007","unstructured":"Tart, A. H., Walker, M. J. & Musser, J. M. New understanding of the group A Streptococcus pathogenesis cycle. Trends Microbiol 15, 318\u2013325 (2007).","journal-title":"Trends Microbiol"},{"key":"BFsrep36233_CR7","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1038\/nrmicro2648","volume":"9","author":"JN Cole","year":"2011","unstructured":"Cole, J. N., Barnett, T. C., Nizet, V. & Walker, M. J. Molecular insight into invasive group A streptococcal disease. Nat Rev Microbiol 9, 724\u2013736 (2011).","journal-title":"Nat Rev Microbiol"},{"key":"BFsrep36233_CR8","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1111\/j.1365-2958.1995.mmi_18040671.x","volume":"18","author":"A Camilli","year":"1995","unstructured":"Camilli, A. & Mekalanos, J. J. Use of recombinase gene fusions to identify Vibrio cholerae genes induced during infection. Mol Microbiol 18, 671\u2013683 (1995).","journal-title":"Mol Microbiol"},{"key":"BFsrep36233_CR9","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1016\/0092-8674(83)90311-2","volume":"32","author":"K Abremski","year":"1983","unstructured":"Abremski, K., Hoess, R. & Sternberg, N. Studies on the properties of P1 site-specific recombination: evidence for topologically unlinked products following recombination. Cell 32, 1301\u20131311 (1983).","journal-title":"Cell"},{"key":"BFsrep36233_CR10","doi-asserted-by":"publisher","first-page":"6518","DOI":"10.1128\/IAI.70.12.6518-6523.2002","volume":"70","author":"MJ Angelichio","year":"2002","unstructured":"Angelichio, M. J. & Camilli, A. In vivo expression technology. Infect Immun 70, 6518\u20136523 (2002).","journal-title":"Infect Immun"},{"key":"BFsrep36233_CR11","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1128\/IAI.71.3.1379-1388.2003","volume":"71","author":"B Saviola","year":"2003","unstructured":"Saviola, B., Woolwine, S. C. & Bishai, W. R. Isolation of acid-inducible genes of Mycobacterium tuberculosis with the use of recombinase-based in vivo expression technology. Infect Immun 71, 1379\u20131388 (2003).","journal-title":"Infect Immun"},{"key":"BFsrep36233_CR12","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1111\/j.1365-2958.2004.04418.x","volume":"55","author":"WL Veal-Carr","year":"2005","unstructured":"Veal-Carr, W. L. & Stibitz, S. Demonstration of differential virulence gene promoter activation in vivo in Bordetella pertussis using RIVET. Mol Microbiol 55, 788\u2013798 (2005).","journal-title":"Mol Microbiol"},{"key":"BFsrep36233_CR13","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1046\/j.1365-2958.1998.00741.x","volume":"27","author":"AM Lowe","year":"1998","unstructured":"Lowe, A. M., Beattie, D. T. & Deresiewicz, R. L. Identification of novel staphylococcal virulence genes by in vivo expression technology. Mol Microbiol 27, 967\u2013976 (1998).","journal-title":"Mol Microbiol"},{"key":"BFsrep36233_CR14","doi-asserted-by":"publisher","first-page":"5721","DOI":"10.1128\/JB.186.17.5721-5729.2004","volume":"186","author":"PA Bron","year":"2004","unstructured":"Bron, P. A., Grangette, C., Mercenier, A., de Vos, W. M. & Kleerebezem, M. Identification of Lactobacillus plantarum genes that are induced in the gastrointestinal tract of mice. J Bacteriol 186, 5721\u20135729 (2004).","journal-title":"J Bacteriol"},{"key":"BFsrep36233_CR15","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1128\/IAI.05964-11","volume":"80","author":"KL Frank","year":"2012","unstructured":"Frank, K. L. et al. Use of recombinase-based in vivo expression technology to characterize Enterococcus faecalis gene expression during infection identifies in vivo-expressed antisense RNAs and implicates the protease Eep in pathogenesis. Infect Immun 80, 539\u2013549 (2012).","journal-title":"Infect Immun"},{"key":"BFsrep36233_CR16","doi-asserted-by":"publisher","first-page":"e25","DOI":"10.1371\/journal.pcbi.0010025","volume":"1","author":"MJ de Hoon","year":"2005","unstructured":"de Hoon, M. J., Makita, Y., Nakai, K. & Miyano, S. Prediction of transcriptional terminators in Bacillus subtilis and related species. PLoS Comput Biol 1, e25 (2005).","journal-title":"PLoS Comput Biol"},{"key":"BFsrep36233_CR17","doi-asserted-by":"publisher","first-page":"3628","DOI":"10.1128\/jb.175.11.3628-3635.1993","volume":"175","author":"I Biswas","year":"1993","unstructured":"Biswas, I., Gruss, A., Ehrlich, S. D. & Maguin, E. High-efficiency gene inactivation and replacement system for gram-positive bacteria. J Bacteriol 175, 3628\u20133635 (1993).","journal-title":"J Bacteriol"},{"key":"BFsrep36233_CR18","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1006\/plas.2000.1484","volume":"44","author":"EM Bryan","year":"2000","unstructured":"Bryan, E. M., Bae, T., Kleerebezem, M. & Dunny, G. M. Improved vectors for nisin-controlled expression in gram-positive bacteria. Plasmid 44, 183\u2013190 (2000).","journal-title":"Plasmid"},{"key":"BFsrep36233_CR19","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/0378-1119(93)90011-Q","volume":"137","author":"DJ O\u2019Sullivan","year":"1993","unstructured":"O\u2019Sullivan, D. J. & Klaenhammer, T. R. High- and low-copy-number Lactococcus shuttle cloning vectors with features for clone screening. Gene 137, 227\u2013231 (1993).","journal-title":"Gene"},{"key":"BFsrep36233_CR20","doi-asserted-by":"publisher","first-page":"e61655","DOI":"10.1371\/journal.pone.0061655","volume":"8","author":"FM Alam","year":"2013","unstructured":"Alam, F. M., Turner, C. E., Smith, K., Wiles, S. & Sriskandan, S. Inactivation of the CovR\/S virulence regulator impairs infection in an improved murine model of Streptococcus pyogenes naso-pharyngeal infection. PLoS One 8, e61655 (2013).","journal-title":"PLoS One"},{"key":"BFsrep36233_CR21","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1128\/IAI.01775-05","volume":"75","author":"S Dawid","year":"2007","unstructured":"Dawid, S., Roche, A. M. & Weiser, J. N. The blp bacteriocins of Streptococcus pneumoniae mediate intraspecies competition both in vitro and in vivo. Infection and immunity 75, 443\u2013451 (2007).","journal-title":"Infection and immunity"},{"key":"BFsrep36233_CR22","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1111\/j.1365-2958.2007.05581.x","volume":"63","author":"Y Eran","year":"2007","unstructured":"Eran, Y. et al. Transcriptional regulation of the sil locus by the SilCR signalling peptide and its implications on group A Streptococcus virulence. Mol Microbiol 63, 1209\u20131222 (2007).","journal-title":"Mol Microbiol"},{"key":"BFsrep36233_CR23","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1046\/j.1365-2958.2002.03127.x","volume":"46","author":"C Hidalgo-Grass","year":"2002","unstructured":"Hidalgo-Grass, C. et al. A locus of group A Streptococcus involved in invasive disease and DNA transfer. Mol Microbiol 46, 87\u201399 (2002).","journal-title":"Mol Microbiol"},{"key":"BFsrep36233_CR24","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1007\/s12602-009-9021-z","volume":"2","author":"J Nissen-Meyer","year":"2010","unstructured":"Nissen-Meyer, J., Oppegard, C., Rogne, P., Haugen, H. S. & Kristiansen, P. E. Structure and Mode-of-Action of the Two-Peptide (Class-IIb) Bacteriocins. Probiotics Antimicrob Proteins 2, 52\u201360 (2010).","journal-title":"Probiotics Antimicrob Proteins"},{"key":"BFsrep36233_CR25","doi-asserted-by":"publisher","first-page":"1293","DOI":"10.1046\/j.1365-2958.1997.3111677.x","volume":"23","author":"MJ van Belkum","year":"1997","unstructured":"van Belkum, M. J., Worobo, R. W. & Stiles, M. E. Double-glycine-type leader peptides direct secretion of bacteriocins by ABC transporters: colicin V secretion in Lactococcus lactis. Mol Microbiol 23, 1293\u20131301 (1997).","journal-title":"Mol Microbiol"},{"key":"BFsrep36233_CR26","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1016\/S0140-6736(04)15643-2","volume":"363","author":"C Hidalgo-Grass","year":"2004","unstructured":"Hidalgo-Grass, C. et al. Effect of a bacterial pheromone peptide on host chemokine degradation in group A streptococcal necrotising soft-tissue infections. Lancet 363, 696\u2013703 (2004).","journal-title":"Lancet"},{"key":"BFsrep36233_CR27","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.1128\/AEM.72.2.1459-1466.2006","volume":"72","author":"PA Wescombe","year":"2006","unstructured":"Wescombe, P. A. et al. Production of the lantibiotic salivaricin A and its variants by oral streptococci and use of a specific induction assay to detect their presence in human saliva. Appl Environ Microbiol 72, 1459\u20131466 (2006).","journal-title":"Appl Environ Microbiol"},{"key":"BFsrep36233_CR28","doi-asserted-by":"publisher","first-page":"2737","DOI":"10.1128\/AEM.69.5.2737-2747.2003","volume":"69","author":"PA Wescombe","year":"2003","unstructured":"Wescombe, P. A. & Tagg, J. R. Purification and characterization of streptin, a type A1 lantibiotic produced by Streptococcus pyogenes. Appl Environ Microbiol 69, 2737\u20132747 (2003).","journal-title":"Appl Environ Microbiol"},{"key":"BFsrep36233_CR29","doi-asserted-by":"publisher","first-page":"4668","DOI":"10.1073\/pnas.062526099","volume":"99","author":"JC Smoot","year":"2002","unstructured":"Smoot, J. C. et al. Genome sequence and comparative microarray analysis of serotype M18 group A Streptococcus strains associated with acute rheumatic fever outbreaks. Proceedings of the National Academy of Sciences of the United States of America 99, 4668\u20134673 (2002).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"BFsrep36233_CR30","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1099\/00222615-12-4-397","volume":"12","author":"JR Tagg","year":"1979","unstructured":"Tagg, J. R. & Bannister, L. V. \u201cFingerprinting\u201d beta-haemolytic streptococci by their production of and sensitivity to bacteriocine-like inhibitors. J Med Microbiol 12, 397\u2013411 (1979).","journal-title":"J Med Microbiol"},{"key":"BFsrep36233_CR31","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1128\/aem.55.1.224-228.1989","volume":"55","author":"M van de Guchte","year":"1989","unstructured":"van de Guchte, M., van der Vossen, J. M., Kok, J. & Venema, G. Construction of a lactococcal expression vector: expression of hen egg white lysozyme in Lactococcus lactis subsp. lactis. Appl Environ Microbiol 55, 224\u2013228 (1989).","journal-title":"Appl Environ Microbiol"},{"key":"BFsrep36233_CR32","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1016\/j.meegid.2009.03.002","volume":"9","author":"DE Bessen","year":"2009","unstructured":"Bessen, D. E. Population biology of the human restricted pathogen, Streptococcus pyogenes. Infect Genet Evol 9, 581\u2013593 (2009).","journal-title":"Infect Genet Evol"},{"key":"BFsrep36233_CR33","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1111\/j.1574-6976.1993.tb00012.x","volume":"12","author":"TR Klaenhammer","year":"1993","unstructured":"Klaenhammer, T. R. Genetics of bacteriocins produced by lactic acid bacteria. FEMS Microbiol Rev 12, 39\u201385 (1993).","journal-title":"FEMS Microbiol Rev"},{"key":"BFsrep36233_CR34","doi-asserted-by":"publisher","first-page":"7617","DOI":"10.1073\/pnas.0700440104","volume":"104","author":"SC Corr","year":"2007","unstructured":"Corr, S. C. et al. Bacteriocin production as a mechanism for the antiinfective activity of Lactobacillus salivarius UCC118. Proceedings of the National Academy of Sciences of the United States of America 104, 7617\u20137621 (2007).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"BFsrep36233_CR35","doi-asserted-by":"publisher","first-page":"e17035","DOI":"10.1371\/journal.pone.0017035","volume":"6","author":"D Bogaert","year":"2011","unstructured":"Bogaert, D. et al. Variability and diversity of nasopharyngeal microbiota in children: a metagenomic analysis. PLoS One 6, e17035 (2011).","journal-title":"PLoS One"},{"key":"BFsrep36233_CR36","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1099\/jmm.0.05259-0","volume":"52","author":"T Walls","year":"2003","unstructured":"Walls, T., Power, D. & Tagg, J. Bacteriocin-like inhibitory substance (BLIS) production by the normal flora of the nasopharynx: potential to protect against otitis media? J Med Microbiol 52, 829\u2013833 (2003).","journal-title":"J Med Microbiol"},{"key":"BFsrep36233_CR37","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1128\/AEM.03350-12","volume":"79","author":"T Fiedler","year":"2013","unstructured":"Fiedler, T. et al. Protective mechanisms of respiratory tract Streptococci against Streptococcus pyogenes biofilm formation and epithelial cell infection. Appl Environ Microbiol 79, 1265\u20131276 (2013).","journal-title":"Appl Environ Microbiol"},{"key":"BFsrep36233_CR38","doi-asserted-by":"publisher","first-page":"2003","DOI":"10.1128\/JCM.00290-14","volume":"52","author":"C Plainvert","year":"2014","unstructured":"Plainvert, C. et al. Molecular epidemiology of sil locus in clinical Streptococcus pyogenes strains. J Clin Microbiol 52, 2003\u20132010 (2014).","journal-title":"J Clin Microbiol"},{"key":"BFsrep36233_CR39","doi-asserted-by":"publisher","first-page":"4658","DOI":"10.1073\/pnas.071559398","volume":"98","author":"JJ Ferretti","year":"2001","unstructured":"Ferretti, J. J. et al. Complete genome sequence of an M1 strain of Streptococcus pyogenes. Proceedings of the National Academy of Sciences of the United States of America 98, 4658\u20134663 (2001).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"BFsrep36233_CR40","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1086\/432514","volume":"192","author":"P Sumby","year":"2005","unstructured":"Sumby, P. et al. Evolutionary origin and emergence of a highly successful clone of serotype M1 group a Streptococcus involved multiple horizontal gene transfer events. The Journal of infectious diseases 192, 771\u2013782 (2005).","journal-title":"The Journal of infectious diseases"},{"key":"BFsrep36233_CR41","doi-asserted-by":"publisher","first-page":"5466","DOI":"10.1128\/JB.01265-12","volume":"194","author":"T Miyoshi-Akiyama","year":"2012","unstructured":"Miyoshi-Akiyama, T., Watanabe, S. & Kirikae, T. Complete genome sequence of Streptococcus pyogenes M1 476, isolated from a patient with streptococcal toxic shock syndrome. J Bacteriol 194, 5466 (2012).","journal-title":"J Bacteriol"},{"key":"BFsrep36233_CR42","doi-asserted-by":"publisher","first-page":"e1000651","DOI":"10.1371\/journal.ppat.1000651","volume":"5","author":"I Belotserkovsky","year":"2009","unstructured":"Belotserkovsky, I. et al. Functional analysis of the quorum-sensing streptococcal invasion locus (sil). PLoS Pathog 5, e1000651 (2009).","journal-title":"PLoS Pathog"},{"key":"BFsrep36233_CR43","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1111\/j.1365-2958.1995.mmi_17030515.x","volume":"17","author":"K Venema","year":"1995","unstructured":"Venema, K. et al. Functional analysis of the pediocin operon of Pediococcus acidilactici PAC1.0: PedB is the immunity protein and PedD is the precursor processing enzyme. Mol Microbiol 17, 515\u2013522 (1995).","journal-title":"Mol Microbiol"},{"key":"BFsrep36233_CR44","doi-asserted-by":"publisher","first-page":"3384","DOI":"10.1074\/jbc.272.6.3384","volume":"272","author":"LE Quadri","year":"1997","unstructured":"Quadri, L. E., Yan, L. Z., Stiles, M. E. & Vederas, J. C. Effect of amino acid substitutions on the activity of carnobacteriocin B2. Overproduction of the antimicrobial peptide, its engineered variants, and its precursor in Escherichia coli. The Journal of biological chemistry 272, 3384\u20133388 (1997).","journal-title":"The Journal of biological chemistry"},{"key":"BFsrep36233_CR45","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1111\/j.1365-2958.1995.tb02295.x","volume":"16","author":"LS Havarstein","year":"1995","unstructured":"Havarstein, L. S., Diep, D. B. & Nes, I. F. A family of bacteriocin ABC transporters carry out proteolytic processing of their substrates concomitant with export. Mol Microbiol 16, 229\u2013240 (1995).","journal-title":"Mol Microbiol"},{"key":"BFsrep36233_CR46","doi-asserted-by":"publisher","first-page":"D343","DOI":"10.1093\/nar\/gkv1118","volume":"44","author":"ND Rawlings","year":"2016","unstructured":"Rawlings, N. D., Barrett, A. J. & Finn, R. Twenty years of the MEROPS database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res 44, D343\u2013D350 (2016).","journal-title":"Nucleic Acids Res"},{"key":"BFsrep36233_CR47","doi-asserted-by":"publisher","first-page":"8484","DOI":"10.1074\/jbc.274.13.8484","volume":"274","author":"CM Franke","year":"1999","unstructured":"Franke, C. M., Tiemersma, J., Venema, G. & Kok, J. Membrane topology of the lactococcal bacteriocin ATP-binding cassette transporter protein LcnC. Involvement of LcnC in lactococcin a maturation. The Journal of biological chemistry 274, 8484\u20138490 (1999).","journal-title":"The Journal of biological chemistry"},{"key":"BFsrep36233_CR48","doi-asserted-by":"publisher","first-page":"843","DOI":"10.1007\/s00203-015-1120-5","volume":"197","author":"G Pal","year":"2015","unstructured":"Pal, G. & Srivastava, S. In vitro activity of a recombinant ABC transporter protein in the processing of plantaricin E pre-peptide. Arch Microbiol 197, 843\u2013849 (2015).","journal-title":"Arch Microbiol"},{"key":"BFsrep36233_CR49","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/j.resmic.2013.03.015","volume":"164","author":"R Lloubes","year":"2013","unstructured":"Lloubes, R., Bernadac, A., Houot, L. & Pommier, S. Non classical secretion systems. Research in microbiology 164, 655\u2013663 (2013).","journal-title":"Research in microbiology"},{"key":"BFsrep36233_CR50","doi-asserted-by":"publisher","first-page":"1854","DOI":"10.1128\/IAI.01306-08","volume":"77","author":"AE Kizy","year":"2009","unstructured":"Kizy, A. E. & Neely, M. N. First Streptococcus pyogenes signature-tagged mutagenesis screen identifies novel virulence determinants. Infect Immun 77, 1854\u20131865 (2009).","journal-title":"Infect Immun"},{"key":"BFsrep36233_CR51","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.cell.2013.12.007","volume":"156","author":"M Baruch","year":"2014","unstructured":"Baruch, M. et al. An extracellular bacterial pathogen modulates host metabolism to regulate its own sensing and proliferation. Cell 156, 97\u2013108 (2014).","journal-title":"Cell"},{"key":"BFsrep36233_CR52","doi-asserted-by":"publisher","first-page":"3256","DOI":"10.1128\/JB.01768-06","volume":"189","author":"U Wegmann","year":"2007","unstructured":"Wegmann, U. et al. Complete genome sequence of the prototype lactic acid bacterium Lactococcus lactis subsp. cremoris MG1363. J Bacteriol 189, 3256\u20133270 (2007).","journal-title":"J Bacteriol"},{"key":"BFsrep36233_CR53","unstructured":"Sambrook, J. & Russell, D. W. Molecular Cloning: A Laboratory Manual. 3rd edn (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N. Y., 2001)."},{"key":"BFsrep36233_CR54","doi-asserted-by":"publisher","first-page":"e1004155","DOI":"10.1371\/journal.ppat.1004155","volume":"10","author":"KJ Kasper","year":"2014","unstructured":"Kasper, K. J. et al. Bacterial superantigens promote acute nasopharyngeal infection by Streptococcus pyogenes in a human MHC Class II-dependent manner. PLoS Pathog 10, e1004155 (2014).","journal-title":"PLoS Pathog"},{"key":"BFsrep36233_CR55","doi-asserted-by":"publisher","first-page":"1805","DOI":"10.1128\/JCM.40.5.1805-1810.2002","volume":"40","author":"JC Smoot","year":"2002","unstructured":"Smoot, J. C., Korgenski, E. K., Daly, J. A., Veasy, L. G. & Musser, J. M. Molecular analysis of group A Streptococcus type emm18 isolates temporally associated with acute rheumatic fever outbreaks in Salt Lake City, Utah. J Clin Microbiol 40, 1805\u20131810 (2002).","journal-title":"J Clin Microbiol"},{"key":"BFsrep36233_CR56","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1093\/protein\/14.12.993","volume":"14","author":"RB Kapust","year":"2001","unstructured":"Kapust, R. B. et al. Tobacco etch virus protease: mechanism of autolysis and rational design of stable mutants with wild-type catalytic proficiency. Protein Eng 14, 993\u20131000 (2001).","journal-title":"Protein Eng"},{"key":"BFsrep36233_CR57","doi-asserted-by":"crossref","first-page":"3119","DOI":"10.1128\/aem.55.12.3119-3123.1989","volume":"55","author":"H Holo","year":"1989","unstructured":"Holo, H. & Nes, I. F. High-Frequency Transformation, by Electroporation, of Lactococcus lactis subsp. cremoris Grown with Glycine in Osmotically Stabilized Media. Appl Environ Microbiol 55, 3119\u20133123 (1989).","journal-title":"Appl Environ Microbiol"},{"key":"BFsrep36233_CR58","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1016\/0378-1119(95)00652-4","volume":"167","author":"AM Guerout-Fleury","year":"1995","unstructured":"Guerout-Fleury, A. M., Shazand, K., Frandsen, N. & Stragier, P. Antibiotic-resistance cassettes for Bacillus subtilis. Gene 167, 335\u2013336 (1995).","journal-title":"Gene"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep36233.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep36233","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep36233.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T01:39:32Z","timestamp":1672882772000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep36233"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,3]]},"references-count":58,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,21]]}},"alternative-id":["BFsrep36233"],"URL":"https:\/\/doi.org\/10.1038\/srep36233","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,3]]},"assertion":[{"value":"23 February 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 October 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 November 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"36233"}}