1932

Abstract

Spore formation and germination are essential for the bacterial pathogen to transmit infection. Despite the importance of these developmental processes to the infection cycle of , the molecular mechanisms underlying how this obligate anaerobe forms infectious spores and how these spores germinate to initiate infection were largely unknown until recently. Work in the last decade has revealed that uses a distinct mechanism for sensing and transducing germinant signals relative to previously characterized spore formers. The spore assembly pathway also exhibits notable differences relative to spp., where spore formation has been more extensively studied. For both these processes, factors that are conserved only in or the related family are employed, and even highly conserved spore proteins can have differential functions or requirements in compared to other spore formers. This review summarizes our current understanding of the mechanisms controlling spore formation and germination and describes strategies for inhibiting these processes to prevent infection and disease recurrence.

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2020-09-08
2024-12-09
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Literature Cited

  1. 1. 
    Abecasis AB, Serrano M, Alves R, Quintais L, Pereira-Leal JB, Henriques AO 2013. A genomic signature and the identification of new sporulation genes. J. Bacteriol. 195:2101–15
    [Google Scholar]
  2. 2. 
    Abhyankar W, Hossain AH, Djajasaputra A, Permpoonpattana P, Ter Beek A et al. 2013. In pursuit of protein targets: proteomic characterization of bacterial spore outer layers. J. Proteome Res. 12:4507–21
    [Google Scholar]
  3. 3. 
    Abt MC, McKenney PT, Pamer EG 2016. Clostridium difficile colitis: pathogenesis and host defence. Nat. Rev. Microbiol. 14:10609–20
    [Google Scholar]
  4. 4. 
    Adams CM, Eckenroth BE, Putnam EE, Doublie S, Shen A 2013. Structural and functional analysis of the CspB protease required for Clostridium spore germination. PLOS Pathog 9:e1003165
    [Google Scholar]
  5. 5. 
    Alabdali YAJ, Oatley P, Kirk JA, Fagan RP 2019. A cortex-specific PBP contributes to cephalosporin resistance in Clostridium difficile. bioRxiv 715458
  6. 6. 
    Aldape MJ, Packham AE, Heeney DD, Rice SN, Bryant AE, Stevens DL 2017. Fidaxomicin reduces early toxin A and B production and sporulation in Clostridium difficile in vitro. J. Med. Microbiol. 66:1393–99
    [Google Scholar]
  7. 7. 
    Alves Feliciano C, Douche T, Giai Gianetto Q, Matondo M, Martin-Verstraete I, Dupuy B 2019. CotL, a new morphogenetic spore coat protein of Clostridium difficile. Environ. . Microbiol 21:984–1003
    [Google Scholar]
  8. 8. 
    Antunes A, Camiade E, Monot M, Courtois E, Barbut F et al. 2012. Global transcriptional control by glucose and carbon regulator CcpA in Clostridium difficile. . Nucleic Acids Res 40:10701–18
    [Google Scholar]
  9. 9. 
    Antunes W, Pereira FC, Feliciano CA, Saujet L, dos Vultos T et al. 2018. Structure and assembly of a Clostridioides difficile spore polar appendage. bioRXiv 468637
  10. 10. 
    Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T et al. 2011. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331:337–41
    [Google Scholar]
  11. 11. 
    Babakhani F, Bouillaut L, Gomez A, Sears P, Nguyen L, Sonenshein AL 2012. Fidaxomicin inhibits spore production in Clostridium difficile. Clin. Infect. Dis 55:Suppl. 2S162–69
    [Google Scholar]
  12. 12. 
    Bhattacharjee D, McAllister KN, Sorg JA 2016. Germinants and their receptors in clostridia. J. Bacteriol. 198:202767–75
    [Google Scholar]
  13. 13. 
    Bhattacharjee D, Sorg JA. 2018. Conservation of the “outside-in” germination pathway in Paraclostridium bifermentans. Front. Microbiol 9:2487
    [Google Scholar]
  14. 14. 
    Calderon-Romero P, Castro-Cordova P, Reyes-Ramirez R, Milano-Cespedes M, Guerrero-Araya E et al. 2018. Clostridium difficile exosporium cysteine-rich proteins are essential for the morphogenesis of the exosporium layer, spore resistance, and affect C. difficile pathogenesis. PLOS Pathog 14:e1007199
    [Google Scholar]
  15. 15. 
    Camp AH, Losick R. 2009. A feeding tube model for activation of a cell-specific transcription factor during sporulation in Bacillus subtilis. . Genes Dev 23:1014–24
    [Google Scholar]
  16. 16. 
    Carlson PE Jr, Walk ST, Bourgis AE, Liu MW, Kopliku F et al. 2013. The relationship between phenotype, ribotype, and clinical disease in human Clostridium difficile isolates. Anaerobe 24:109–16
    [Google Scholar]
  17. 17. 
    Cent. Dis. Control Prev 2019. Antibiotic resistance threats in the United States AR Threats Rep., Cent. Dis. Control Prev Atlanta, GA: https://www.cdc.gov/drugresistance/biggest-threats.html
    [Google Scholar]
  18. 18. 
    Chastanet A, Losick R. 2007. Engulfment during sporulation in Bacillus subtilis is governed by a multi-protein complex containing tandemly acting autolysins. Mol. Microbiol. 64:139–52
    [Google Scholar]
  19. 19. 
    Chilton CH, Crowther GS, Ashwin H, Longshaw CM, Wilcox MH 2016. Association of fidaxomicin with C. difficile spores: effects of persistence on subsequent spore recovery, outgrowth and toxin production. PLOS ONE 11:e0161200
    [Google Scholar]
  20. 20. 
    Chilton CH, Pickering DS, Freeman J 2018. Microbiologic factors affecting Clostridium difficile recurrence. Clin. Microbiol. Infect. 24:476–82
    [Google Scholar]
  21. 21. 
    Cokol M, Kuru N, Bicak E, Larkins-Ford J, Aldridge BB 2017. Efficient measurement and factorization of high-order drug interactions in Mycobacterium tuberculosis. Sci. Adv 3:e1701881
    [Google Scholar]
  22. 22. 
    Collery MM, Kuehne SA, McBride SM, Kelly ML, Monot M et al. 2017. What's a SNP between friends: the influence of single nucleotide polymorphisms on virulence and phenotypes of Clostridium difficile strain 630 and derivatives. Virulence 8:767–81
    [Google Scholar]
  23. 23. 
    Coullon H, Rifflet A, Wheeler R, Janoir C, Boneca IG, Candela T 2018. N-Deacetylases required for muramic-δ-lactam production are involved in Clostridium difficile sporulation, germination, and heat resistance. J. Biol. Chem. 293:18040–54
    [Google Scholar]
  24. 24. 
    Daniel RA, Drake S, Buchanan CE, Scholle R, Errington J 1994. The Bacillus subtilis spoVD gene encodes a mother-cell-specific penicillin-binding protein required for spore morphogenesis. J. Mol. Biol. 235:209–20
    [Google Scholar]
  25. 25. 
    Deakin LJ, Clare S, Fagan RP, Dawson LF, Pickard DJ et al. 2012. The Clostridium difficile spo0A gene is a persistence and transmission factor. Infect. Immun. 80:2704–11
    [Google Scholar]
  26. 26. 
    DeFilipp Z, Bloom PP, Torres Soto M, Mansour MK, Sater MRA et al. 2019. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N. Engl. J. Med. 381:2043–50
    [Google Scholar]
  27. 27. 
    Dembek M, Barquist L, Boinett CJ, Cain AK, Mayho M et al. 2015. High-throughput analysis of gene essentiality and sporulation in Clostridium difficile. . mBio 6:e02383
    [Google Scholar]
  28. 28. 
    Dembek M, Kelly A, Barwinska-Sendra A, Tarrant E, Stanley WA et al. 2018. Peptidoglycan degradation machinery in Clostridium difficile forespore engulfment. Mol. Microbiol. 110:390–410
    [Google Scholar]
  29. 29. 
    Dembek M, Stabler RA, Witney AA, Wren BW, Fairweather NF 2013. Transcriptional analysis of temporal gene expression in germinating Clostridium difficile 630 endospores. PLOS ONE 8:e64011
    [Google Scholar]
  30. 30. 
    Diaz AR, Core LJ, Jiang M, Morelli M, Chiang CH et al. 2012. Bacillus subtilis RapA phosphatase domain interaction with its substrate, phosphorylated Spo0F, and its inhibitor, the PhrA peptide. J. Bacteriol. 194:1378–88
    [Google Scholar]
  31. 31. 
    Diaz OR, Sayer CV, Popham DL, Shen A 2018. Clostridium difficile lipoprotein GerS is required for cortex modification and thus spore germination. mSphere 3:e00205–18
    [Google Scholar]
  32. 32. 
    Doan T, Morlot C, Meisner J, Serrano M, Henriques A et al. 2009. Novel secretion apparatus maintains spore integrity and developmental gene expression in Bacillus subtilis. . PLOS Genet 5:e1000566
    [Google Scholar]
  33. 33. 
    Donnelly ML, Fimlaid KA, Shen A 2016. Characterization of Clostridium difficile spores lacking either SpoVAC or dipicolinic acid synthetase. J. Bacteriol. 198:1694–707
    [Google Scholar]
  34. 34. 
    Donnelly ML, Li W, Li YQ, Hinkel L, Setlow P, Shen A 2017. A Clostridium difficile-specific, gel-forming protein required for optimal spore germination. mBio 8:e02085–16
    [Google Scholar]
  35. 35. 
    Driks A, Eichenberger P. 2016. The spore coat. Microbiol. Spectr. 4:2 https://doi.org/10.1128/microbiolspec.TBS-0023-2016
    [Crossref] [Google Scholar]
  36. 36. 
    Edwards AN, Krall EG, McBride SM 2020. Strain-dependent RstA regulation of Clostridioides difficile toxin production and sporulation. J. Bacteriol. 202:2e00586–19
    [Google Scholar]
  37. 37. 
    Edwards AN, McBride SM. 2014. Initiation of sporulation in Clostridium difficile: a twist on the classic model. FEMS Microbiol. Lett. 358:110–18
    [Google Scholar]
  38. 38. 
    Edwards AN, Tamayo R, McBride SM 2016. A novel regulator controls Clostridium difficile sporulation, motility and toxin production. Mol. Microbiol. 100:954–71
    [Google Scholar]
  39. 39. 
    Escobar-Cortes K, Barra-Carrasco J, Paredes-Sabja D 2013. Proteases and sonication specifically remove the exosporium layer of spores of Clostridium difficile strain 630. J. Microbiol. Methods 93:25–31
    [Google Scholar]
  40. 40. 
    Fay A, Meyer P, Dworkin J 2010. Interactions between late-acting proteins required for peptidoglycan synthesis during sporulation. J. Mol. Biol. 399:547–61
    [Google Scholar]
  41. 41. 
    Fimlaid KA, Bond JP, Schutz KC, Putnam EE, Leung JM et al. 2013. Global analysis of the sporulation pathway of Clostridium difficile. . PLOS Genet 9:e1003660
    [Google Scholar]
  42. 42. 
    Fimlaid KA, Jensen O, Donnelly ML, Francis MB, Sorg JA, Shen A 2015. Identification of a novel lipoprotein regulator of Clostridium difficile spore germination. PLOS Pathog 11:10e1005239
    [Google Scholar]
  43. 43. 
    Fimlaid KA, Jensen O, Donnelly ML, Siegrist MS, Shen A 2015. Regulation of Clostridium difficile spore formation by the SpoIIQ and SpoIIIA proteins. PLOS Genet 11:e1005562
    [Google Scholar]
  44. 44. 
    Fimlaid KA, Shen A. 2015. Diverse mechanisms regulate sporulation sigma factor activity in the Firmicutes. Curr. Opin. Microbiol. 24:88–95
    [Google Scholar]
  45. 45. 
    Francis MB, Allen CA, Shrestha R, Sorg JA 2013. Bile acid recognition by the Clostridium difficile germinant receptor, CspC, is important for establishing infection. PLOS Pathog 9:e1003356
    [Google Scholar]
  46. 46. 
    Francis MB, Allen CA, Sorg JA 2015. Spore cortex hydrolysis precedes DPA release during Clostridium difficile spore germination. J. Bacteriol. 197:142276–83
    [Google Scholar]
  47. 47. 
    Francis MB, Sorg JA. 2016. Dipicolinic acid release by germinating Clostridium difficile spores occurs through a mechanosensing mechanism. mSphere 1:e00306–16
    [Google Scholar]
  48. 48. 
    Fukushima T, Yamamoto H, Atrih A, Foster SJ, Sekiguchi J 2002. A polysaccharide deacetylase gene (pdaA) is required for germination and for production of muramic δ-lactam residues in the spore cortex of Bacillus subtilis. J. . Bacteriol 184:6007–15
    [Google Scholar]
  49. 49. 
    Galperin MY, Mekhedov SL, Puigbo P, Smirnov S, Wolf YI, Rigden DJ 2012. Genomic determinants of sporulation in Bacilli and Clostridia: towards the minimal set of sporulation-specific genes. Environ. Microbiol. 14:2870–90
    [Google Scholar]
  50. 50. 
    Ghose C, Eugenis I, Edwards AN, Sun X, McBride SM, Ho DD 2016. Immunogenicity and protective efficacy of Clostridium difficile spore proteins. Anaerobe 37:85–95
    [Google Scholar]
  51. 51. 
    Giel JL, Sorg JA, Sonenshein AL, Zhu J 2010. Metabolism of bile salts in mice influences spore germination in Clostridium difficile. . PLOS ONE 5:e8740
    [Google Scholar]
  52. 52. 
    Gilmore ME, Bandyopadhyay D, Dean AM, Linnstaedt SD, Popham DL 2004. Production of muramic δ-lactam in Bacillus subtilis spore peptidoglycan. J. Bacteriol. 186:80–89
    [Google Scholar]
  53. 53. 
    Girinathan BP, Monot M, Boyle D, McAllister KN, Sorg JA et al. 2017. Effect of tcdR mutation on sporulation in the epidemic Clostridium difficile strain R20291. mSphere 2:1e00383–16
    [Google Scholar]
  54. 54. 
    Girinathan BP, Ou J, Dupuy B, Govind R 2018. Pleiotropic roles of Clostridium difficile sin locus. PLOS Pathog 14:e1006940
    [Google Scholar]
  55. 55. 
    Gomez S, Chaves F, Orellana MA 2017. Clinical, epidemiological and microbiological characteristics of relapse and re-infection in Clostridium difficile infection. Anaerobe 48:147–51
    [Google Scholar]
  56. 56. 
    Henriques AO, Moran CP Jr 2007. Structure, assembly, and function of the spore surface layers. Annu. Rev. Microbiol. 61:555–88
    [Google Scholar]
  57. 57. 
    Hong HA, Ferreira WT, Hosseini S, Anwar S, Hitri K et al. 2017. The spore coat protein CotE facilitates host colonisation by Clostridium difficile. J. Infect. . Dis 216:111452–59
    [Google Scholar]
  58. 58. 
    Howerton A, Patra M, Abel-Santos E 2013. A new strategy for the prevention of Clostridium difficile infection. J. Infect. Dis. 207:1498–504
    [Google Scholar]
  59. 59. 
    Howerton A, Seymour CO, Murugapiran SK, Liao Z, Phan JR et al. 2018. Effect of the synthetic bile salt analog CamSA on the hamster model of Clostridium difficile infection. Antimicrob. Agents Chemother. 62:e02251–17
    [Google Scholar]
  60. 60. 
    Ikeda M, Sato T, Wachi M, Jung HK, Ishino F et al. 1989. Structural similarity among Escherichia coli FtsW and RodA proteins and Bacillus subtilis SpoVE protein, which function in cell division, cell elongation, and spore formation, respectively. J. Bacteriol. 171:6375–78
    [Google Scholar]
  61. 61. 
    Janezic S, Mlakar S, Rupnik M 2018. Dissemination of Clostridium difficile spores between environment and households: dog paws and shoes. Zoonoses Public Health 65:6669–74
    [Google Scholar]
  62. 62. 
    Jones AM, Kuijper EJ, Wilcox MH 2013. Clostridium difficile: a European perspective. J. Infect. 66:115–28
    [Google Scholar]
  63. 63. 
    Kelly A, Salgado PS. 2019. The engulfasome in C. difficile: variations on protein machineries. Anaerobe 60:102091
    [Google Scholar]
  64. 64. 
    Kevorkian Y, Shen A. 2017. Revisiting the role of Csp family proteins in regulating Clostridium difficile spore germination. J. Bacteriol. 199:22e00266–17
    [Google Scholar]
  65. 65. 
    Kevorkian Y, Shirley DJ, Shen A 2016. Regulation of Clostridium difficile spore germination by the CspA pseudoprotease domain. Biochimie 122:243–54
    [Google Scholar]
  66. 66. 
    Kochan TJ, Foley MH, Shoshiev MS, Somers MJ, Carlson PE, Hanna PC 2018. Updates to Clostridium difficile spore germination. J. Bacteriol. 200:16e00218–18
    [Google Scholar]
  67. 67. 
    Kochan TJ, Shoshiev MS, Hastie JL, Somers MJ, Plotnick YM et al. 2018. Germinant synergy facilitates Clostridium difficile spore germination under physiological conditions. mSphere 3:5e00335–18
    [Google Scholar]
  68. 68. 
    Kochan TJ, Somers MJ, Kaiser AM, Shoshiev MS, Hagan AK et al. 2017. Intestinal calcium and bile salts facilitate germination of Clostridium difficile spores. PLOS Pathog 13:e1006443
    [Google Scholar]
  69. 69. 
    Koenigsknecht MJ, Theriot CM, Bergin IL, Schumacher CA, Schloss PD, Young VB 2015. Dynamics and establishment of Clostridium difficile infection in the murine gastrointestinal tract. Infect. Immun. 83:934–41
    [Google Scholar]
  70. 70. 
    Kumar N, Browne HP, Viciani E, Forster SC, Clare S et al. 2019. Adaptation of host transmission cycle during Clostridium difficile speciation. Nat. Genet. 51:1315–20
    [Google Scholar]
  71. 71. 
    Lawley TD, Clare S, Deakin LJ, Goulding D, Yen JL et al. 2010. Use of purified Clostridium difficile spores to facilitate evaluation of health care disinfection regimens. Appl. Environ. Microbiol. 76:6895–900
    [Google Scholar]
  72. 72. 
    Lewis BB, Pamer EG. 2017. Microbiota-based therapies for Clostridium difficile and antibiotic-resistant enteric infections. Annu. Rev. Microbiol. 71:157–78
    [Google Scholar]
  73. 73. 
    Malyshev D, Baillie L. 2019. Surface morphology differences in Clostridium difficile spores, based on different strains and methods of purification. Anaerobe 61:102078
    [Google Scholar]
  74. 74. 
    McBride SM, Sonenshein AL. 2011. The dlt operon confers resistance to cationic antimicrobial peptides in Clostridium difficile. . Microbiology 157:1457–65
    [Google Scholar]
  75. 75. 
    McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC et al. 2018. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin. Infect. Dis. 66:987–94
    [Google Scholar]
  76. 76. 
    Meeske AJ, Riley EP, Robins WP, Uehara T, Mekalanos JJ et al. 2016. SEDS proteins are a widespread family of bacterial cell wall polymerases. Nature 537:634–38
    [Google Scholar]
  77. 77. 
    Meeske AJ, Sham LT, Kimsey H, Koo BM, Gross CA et al. 2015. MurJ and a novel lipid II flippase are required for cell wall biogenesis in Bacillus subtilis. . PNAS 112:6437–42
    [Google Scholar]
  78. 78. 
    Merrigan M, Venugopal A, Mallozzi M, Roxas B, Viswanathan VK et al. 2010. Human hypervirulent Clostridium difficile strains exhibit increased sporulation as well as robust toxin production. J. Bacteriol. 192:4904–11
    [Google Scholar]
  79. 79. 
    Miyata S, Kozuka S, Yasuda Y, Chen Y, Moriyama R et al. 1997. Localization of germination-specific spore-lytic enzymes in Clostridium perfringens S40 spores detected by immunoelectron microscopy. FEMS Microbiol. Lett. 152:243–47
    [Google Scholar]
  80. 80. 
    Moore P, Kyne L, Martin A, Solomon K 2013. Germination efficiency of clinical Clostridium difficile spores and correlation with ribotype, disease severity and therapy failure. J. Med. Microbiol. 62:1405–13
    [Google Scholar]
  81. 81. 
    Murphy JM, Mace PD, Eyers PA 2017. Live and let die: insights into pseudoenzyme mechanisms from structure. Curr. Opin. Struct. Biol. 47:95–104
    [Google Scholar]
  82. 82. 
    Nawrocki KL, Edwards AN, Daou N, Bouillaut L, McBride SM 2016. CodY-dependent regulation of sporulation in Clostridium difficile. J. . Bacteriol 198:2113–30
    [Google Scholar]
  83. 83. 
    Nerandzic MM, Donskey CJ. 2010. Triggering germination represents a novel strategy to enhance killing of Clostridium difficile spores. PLOS ONE 5:e12285
    [Google Scholar]
  84. 84. 
    Ng YK, Ehsaan M, Philip S, Collery MM, Janoir C et al. 2013. Expanding the repertoire of gene tools for precise manipulation of the Clostridium difficile genome: allelic exchange using pyrE alleles. PLOS ONE 8:e56051
    [Google Scholar]
  85. 85. 
    Oka K, Osaki T, Hanawa T, Kurata S, Okazaki M et al. 2012. Molecular and microbiological characterization of Clostridium difficile isolates from single, relapse, and reinfection cases. J. Clin. Microbiol. 50:915–21
    [Google Scholar]
  86. 86. 
    Oliveira PH, Ribis JW, Garrett EM, Trzilova D, Kim A et al. 2020. Epigenomic characterization of Clostridioides difficile finds a conserved DNA methyltransferase that mediates sporulation and pathogenesis. Nat. Microbiol. 5:166–80
    [Google Scholar]
  87. 87. 
    Orsburn B, Melville SB, Popham DL 2008. Factors contributing to heat resistance of Clostridium perfringens endospores. Appl. Environ. Microbiol. 74:3328–35
    [Google Scholar]
  88. 88. 
    Ottmann C, Rose R, Huttenlocher F, Cedzich A, Hauske P et al. 2009. Structural basis for Ca2+-independence and activation by homodimerization of tomato subtilase 3. PNAS 106:17223–28
    [Google Scholar]
  89. 89. 
    Paredes-Sabja D, Setlow P, Sarker M 2011. Germination of spores of Bacillales and Clostridiales species: mechanisms and proteins involved. Trends Microbiol 19:85–94
    [Google Scholar]
  90. 90. 
    Peluso EA, Updegrove TB, Chen J, Shroff H, Ramamurthi KS 2019. A 2-dimensional ratchet model describes assembly initiation of a specialized bacterial cell surface. PNAS 116:21789–99
    [Google Scholar]
  91. 91. 
    Perchat S, Talagas A, Poncet S, Lazar N, Li de la Sierra-Gallay I et al. 2016. How quorum sensing connects sporulation to necrotrophism in Bacillus thuringiensis. . PLOS Pathog 12:e1005779
    [Google Scholar]
  92. 92. 
    Pereira FC, Saujet L, Tome AR, Serrano M, Monot M et al. 2013. The spore differentiation pathway in the enteric pathogen Clostridium difficile. . PLOS Genet 9:e1003782
    [Google Scholar]
  93. 93. 
    Permpoonpattana P, Phetcharaburanin J, Mikelsone A, Dembek M, Tan S et al. 2013. Functional characterization of Clostridium difficile spore coat proteins. J. Bacteriol. 195:1492–503
    [Google Scholar]
  94. 94. 
    Phetcharaburanin J, Hong HA, Colenutt C, Bianconi I, Sempere L et al. 2014. The spore-associated protein BclA1 affects the susceptibility of animals to colonization and infection by Clostridium difficile. Mol. Microbiol 92:1025–38
    [Google Scholar]
  95. 95. 
    Pishdadian K, Fimlaid KA, Shen A 2015. SpoIIID-mediated regulation of σK function during Clostridium difficile sporulation. Mol. Microbiol. 95:189–208
    [Google Scholar]
  96. 96. 
    Pizarro-Guajardo M, Calderon-Romero P, Castro-Cordova P, Mora-Uribe P, Paredes-Sabja D 2016. Ultrastructural variability of the exosporium layer of Clostridium difficile spores. Appl. Environ. Microbiol. 82:2202–9
    [Google Scholar]
  97. 97. 
    Pizarro-Guajardo M, Olguin-Araneda V, Barra-Carrasco J, Brito-Silva C, Sarker MR, Paredes-Sabja D 2014. Characterization of the collagen-like exosporium protein, BclA1, of Clostridium difficile spores. Anaerobe 25:18–30
    [Google Scholar]
  98. 98. 
    Popham DL, Bernhards CB. 2015. Spore peptidoglycan. Microbiol. Spectr. 3:6 https://doi.org/10.1128/microbiolspec.TBS-0005-2012
    [Crossref] [Google Scholar]
  99. 99. 
    Popham DL, Helin J, Costello CE, Setlow P 1996. Muramic lactam in peptidoglycan of Bacillus subtilis spores is required for spore outgrowth but not for spore dehydration or heat resistance. PNAS 93:15405–10
    [Google Scholar]
  100. 100. 
    Putnam EE, Nock AM, Lawley TD, Shen A 2013. SpoIVA and SipL are Clostridium difficile spore morphogenetic proteins. J. Bacteriol. 195:1214–25
    [Google Scholar]
  101. 101. 
    Rabi R, Larcombe S, Mathias R, McGowan S, Awad M, Lyras D 2018. Clostridium sordellii outer spore proteins maintain spore structural integrity and promote bacterial clearance from the gastrointestinal tract. PLOS Pathog 14:e1007004
    [Google Scholar]
  102. 102. 
    Rabi R, Turnbull L, Whitchurch CB, Awad M, Lyras D 2017. Structural characterization of Clostridium sordellii spores of diverse human, animal, and environmental origin and comparison to Clostridium difficile spores. mSphere 2:5e00343-17
    [Google Scholar]
  103. 103. 
    Ramamurthi KS, Losick R. 2008. ATP-driven self-assembly of a morphogenetic protein in Bacillus subtilis. Mol. Cell 31:406–14
    [Google Scholar]
  104. 104. 
    Ramirez-Guadiana FH, Meeske AJ, Rodrigues CDA, Barajas-Ornelas RDC, Kruse AC, Rudner DZ 2017. A two-step transport pathway allows the mother cell to nurture the developing spore in Bacillus subtilis. . PLOS Genet 13:e1007015
    [Google Scholar]
  105. 105. 
    Regan G, Itaya M, Piggot PJ 2012. Coupling of σG activation to completion of engulfment during sporulation of Bacillus subtilis survives large perturbations to DNA translocation and replication. J. Bacteriol. 194:6264–71
    [Google Scholar]
  106. 106. 
    Ribis JW, Fimlaid KA, Shen A 2018. Differential requirements for conserved peptidoglycan hydrolases during Clostridium difficile spore formation. Mol. Microbiol. 110:370–89
    [Google Scholar]
  107. 107. 
    Ribis JW, Ravichandran P, Putnam EE, Pishdadian K, Shen A 2017. The conserved spore coat protein SpoVM is largely dispensable in Clostridium difficile spore formation. mSphere 2:5e00315-17
    [Google Scholar]
  108. 108. 
    Ridlon JM, Kang DJ, Hylemon PB, Bajaj JS 2014. Bile acids and the gut microbiome. Curr. Opin. Gastroenterol. 30:332–38
    [Google Scholar]
  109. 109. 
    Rohlfing AE, Eckenroth BE, Forster ER, Kevorkian Y, Donnelly ML et al. 2019. The CspC pseudoprotease regulates germination of Clostridioides difficile spores in response to multiple environmental signals. PLOS Genet 15:e1008224
    [Google Scholar]
  110. 110. 
    Saujet L, Pereira FC, Henriques AO, Martin-Verstraete I 2014. The regulatory network controlling spore formation in Clostridium difficile. FEMS Microbiol. . Lett 358:1–10
    [Google Scholar]
  111. 111. 
    Saujet L, Pereira FC, Serrano M, Soutourina O, Monot M et al. 2013. Genome-wide analysis of cell type-specific gene transcription during spore formation in Clostridium difficile. . PLOS Genet 9:e1003756
    [Google Scholar]
  112. 112. 
    Sebaihia M, Wren B, Mullany P, Fairweather N, Minton N et al. 2006. The multidrug-resistant human pathogen Clostridium difficile has a highly mobile, mosaic genome. Nat. Genet. 38:779–86
    [Google Scholar]
  113. 113. 
    Serrano M, Crawshaw AD, Dembek M, Monteiro JM, Pereira FC et al. 2016. The SpoIIQ-SpoIIIAH complex of Clostridium difficile controls forespore engulfment and late stages of gene expression and spore morphogenesis. Mol. Microbiol. 100:204–28
    [Google Scholar]
  114. 114. 
    Serrano M, Kint N, Pereira FC, Saujet L, Boudry P et al. 2016. A recombination directionality factor controls the cell type-specific activation of σK and the fidelity of spore development in Clostridium difficile. . PLOS Genet 12:e1006312
    [Google Scholar]
  115. 115. 
    Setlow P. 2014. Germination of spores of Bacillus species: what we know and do not know. J. Bacteriol. 196:1297–305
    [Google Scholar]
  116. 116. 
    Setlow P, Wang S, Li YQ 2017. Germination of spores of the orders Bacillales and Clostridiales. Annu. Rev. Microbiol 71:459–77
    [Google Scholar]
  117. 117. 
    Sharma SK, Yip C, Esposito EX, Sharma PV, Simon MP et al. 2018. The design, synthesis, and characterizations of spore germination inhibitors effective against an epidemic strain of Clostridium difficile. J. Med. Chem 61:6759–78
    [Google Scholar]
  118. 118. 
    Shen A. 2015. A gut odyssey: the impact of the microbiota on Clostridium difficile spore formation and germination. PLOS Pathog 11:e1005157
    [Google Scholar]
  119. 119. 
    Shen A, Edwards AN, Sarker MR, Paredes-Sabja D 2019. Sporulation and germination in clostridial pathogens. Microbiol. Spectr. 7:6 https://doi.org/10.1128/microbiolspec.GPP3-0017-2018
    [Crossref] [Google Scholar]
  120. 120. 
    Shimamoto S, Moriyama R, Sugimoto K, Miyata S, Makino S 2001. Partial characterization of an enzyme fraction with protease activity which converts the spore peptidoglycan hydrolase (SleC) precursor to an active enzyme during germination of Clostridium perfringens S40 spores and analysis of a gene cluster involved in the activity. J. Bacteriol. 183:3742–51
    [Google Scholar]
  121. 121. 
    Shinde U, Thomas G. 2011. Insights from bacterial subtilases into the mechanisms of intramolecular chaperone-mediated activation of furin. Methods Mol. Biol. 768:59–106
    [Google Scholar]
  122. 122. 
    Shrestha R, Cochran AM, Sorg JA 2019. The requirement for co-germinants during Clostridium difficile spore germination is influenced by mutations in yabG and cspA. . PLOS Pathog 15:e1007681
    [Google Scholar]
  123. 123. 
    Shrestha R, Lockless SW, Sorg JA 2017. A Clostridium difficile alanine racemase affects spore germination and accommodates serine as a substrate. J. Biol. Chem. 292:10735–42
    [Google Scholar]
  124. 124. 
    Shrestha R, Sorg JA. 2017. Hierarchical recognition of amino acid co-germinants during Clostridioides difficile spore germination. Anaerobe 49:41–47
    [Google Scholar]
  125. 125. 
    Shrestha R, Sorg JA. 2019. Terbium chloride influences Clostridium difficile spore germination. Anaerobe 58:80–88
    [Google Scholar]
  126. 126. 
    Sinai L, Rosenberg A, Smith Y, Segev E, Ben-Yehuda S 2015. The molecular timeline of a reviving bacterial spore. Mol. Cell 57:695–707
    [Google Scholar]
  127. 127. 
    Smith K, Bayer ME, Youngman P 1993. Physical and functional characterization of the Bacillus subtilis spoIIM gene. J. Bacteriol. 175:3607–17
    [Google Scholar]
  128. 128. 
    Sorg JA, Sonenshein AL. 2008. Bile salts and glycine as cogerminants for Clostridium difficile spores. J. Bacteriol. 190:2505–12
    [Google Scholar]
  129. 129. 
    Sorg JA, Sonenshein AL. 2009. Chenodeoxycholate is an inhibitor of Clostridium difficile spore germination. J. Bacteriol. 191:1115–17
    [Google Scholar]
  130. 130. 
    Sorg JA, Sonenshein AL. 2010. Inhibiting the initiation of Clostridium difficile spore germination using analogs of chenodeoxycholic acid, a bile acid. J. Bacteriol. 192:4983–90
    [Google Scholar]
  131. 131. 
    Srikhanta YN, Hutton ML, Awad MM, Drinkwater N, Singleton J et al. 2019. Cephamycins inhibit pathogen sporulation and effectively treat recurrent Clostridioides difficile infection. Nat. Microbiol. 4:2237–45
    [Google Scholar]
  132. 132. 
    Stewart GC. 2015. The exosporium layer of bacterial spores: a connection to the environment and the infected host. Microbiol. Mol. Biol. Rev. 79:437–57
    [Google Scholar]
  133. 133. 
    Stoltz KL, Erickson R, Staley C, Weingarden AR, Romens E et al. 2017. Synthesis and biological evaluation of bile acid analogues inhibitory to Clostridium difficile spore germination. J. Med. Chem. 60:3451–71
    [Google Scholar]
  134. 134. 
    Tabak YP, Srinivasan A, Yu KC, Kurtz SG, Gupta V et al. 2019. Hospital-level high-risk antibiotic use in relation to hospital-associated Clostridioides difficile infections: retrospective analysis of 2016–2017 data from US hospitals. Infect. Control Hosp. Epidemiol. 40:1229–35
    [Google Scholar]
  135. 135. 
    Tan IS, Ramamurthi KS. 2014. Spore formation in Bacillus subtilis. Environ. Microbiol. Rep 6:212–25
    [Google Scholar]
  136. 136. 
    Tan IS, Weiss CA, Popham DL, Ramamurthi KS 2015. A quality-control mechanism removes unfit cells from a population of sporulating bacteria. Dev. Cell 34:682–93
    [Google Scholar]
  137. 137. 
    Thanissery R, Winston JA, Theriot CM 2017. Inhibition of spore germination, growth, and toxin activity of clinically relevant C. difficile strains by gut microbiota derived secondary bile acids. Anaerobe 45:86–100
    [Google Scholar]
  138. 138. 
    Theriot CM, Young VB. 2015. Interactions between the gastrointestinal microbiome and Clostridium difficile. Annu. Rev. Microbiol 69:445–61
    [Google Scholar]
  139. 139. 
    Touchette MH, Benito de la Puebla H, Ravichandran P, Shen A 2019. SpoIVA-SipL complex formation is essential for Clostridioides difficile spore assembly. J. Bacteriol. 201:8e00042-19
    [Google Scholar]
  140. 140. 
    Underwood S, Guan S, Vijayasubhash V, Baines S, Graham L et al. 2009. Characterization of the sporulation initiation pathway of Clostridium difficile and its role in toxin production. J. Bacteriol. 191:7296–305
    [Google Scholar]
  141. 141. 
    van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG et al. 2013. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med 368:407–15
    [Google Scholar]
  142. 142. 
    Wang S, Setlow B, Conlon E, Lyon J, Imamura D et al. 2006. The forespore line of gene expression in Bacillus subtilis. J. Mol. Biol 358:16–37
    [Google Scholar]
  143. 143. 
    Wang S, Shen A, Setlow P, Li YQ 2015. Characterization of the dynamic germination of individual Clostridium difficile spores using Raman spectroscopy and differential interference contrast microscopy. J. Bacteriol. 197:142361–73
    [Google Scholar]
  144. 144. 
    Webb BJ, Brunner A, Lewis J, Ford CD, Lopansri BK 2019. Repurposing an old drug for a new epidemic: ursodeoxycholic acid to prevent recurrent Clostridioides difficile infection. Clin. Infect. Dis. 68:498–500
    [Google Scholar]
  145. 145. 
    Weingarden AR, Chen C, Zhang N, Graiziger CT, Dosa PI et al. 2016. Ursodeoxycholic acid inhibits Clostridium difficile spore germination and vegetative growth, and prevents the recurrence of ileal pouchitis associated with the infection. J. Clin. Gastroenterol. 50:624–30
    [Google Scholar]
  146. 146. 
    Wetzel D, McBride SM. 2019. The impact of pH on Clostridioides difficile sporulation and physiology. Appl. Environ. Microbiol. 86:4e02706-19
    [Google Scholar]
  147. 147. 
    Zhu D, Sorg JA, Sun X 2018. Clostridioides difficile biology: sporulation, germination, and corresponding therapies for C. difficile infection. Front. Cell Infect. Microbiol. 8:29
    [Google Scholar]
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